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Apoptosis of uninfected cells induced by HIV envelope glycoproteins


Apoptosis, or programmed cell death, is a key event in biologic homeostasis but is also involved in the pathogenesis of many human diseases including human immunodeficiency virus (HIV) infection. Although multiple mechanisms contribute to the gradual T cell decline that occurs in HIV-infected patients, programmed cell death of uninfected bystander T lymphocytes, including CD4+ and CD8+ T cells, is an important event leading to immunodeficiency. The HIV envelope glycoproteins (Env) play a crucial role in transducing this apoptotic signal after binding to its receptors, the CD4 molecule and a coreceptor, essentially CCR5 and CXCR4. Depending on Env presentation, the receptor involved and the complexity of target cell contact, apoptosis induction is related to death receptor and/or mitochondria-dependent pathways. This review summarizes current knowledge of Env-mediated cell death leading to T cell depletion and clinical complications and covers the sometimes conflicting studies that address the possible mechanisms of T cell death.


HIV infection usually leads to progressive decline in functionality and number of CD4+ T lymphocytes, resulting in AIDS development [1]. Despite intensive studies, several crucial questions remain to be addressed about the mechanisms through which HIV infection induces T cell death and this subject is one of the most controversial issues in AIDS research.

First, T cell loss could be due to direct destruction by the virus. HIV infection results in high T cell activation and turnover, and accelerates both production and destruction of CD4+ T cells [1, 2]. Using a mathematical model, Mohri and collaborators have demonstrated that T cell depletion observed in HIV-1 infection was due to an increased turnover of T lymphocytes rather than a decrease in cellular production [3], but the dynamics of T cells in HIV-infected patients remain controversial [4].

A strong immune response is a priori beneficial in controlling viral replication. However, independently of viral load, a chronic, heightened activation of the immune system may contribute in a direct manner to progressive CD4+ T cell depletion [4, 5]. Two observations corroborate this hypothesis. First, sooty mangabeys, the natural host of simian immunodeficiency virus (SIV), which do not develop AIDS, support high levels of viral replication but fail to exhibit a clear increase in immune activation [6]. In contrast, SIV experimentally transferred to rhesus macaques induces a dramatic increase in immune activation and rapid progression to AIDS and death. In the same way, HIV-1 and HIV-2-infected patients with similar degree of CD4+ T cell depletion show large differences in viral load [7]. CD4+ T cell loss during the chronic phase of HIV/SIV infection is thus more directly related to the overall immune response than the rate of virus replication. Immune activation could drive the progression of HIV disease by destabilizing or progressively changing the homeostatic states of resting T cell populations.

Second, T cell apoptosis has been proposed as early as 1991 as another mechanism responsible for T cell depletion in patients infected with HIV-1 [8, 9] and an extensive body of literature since then has supported this hypothesis. In addition, there is a correlation between the extent of apoptosis and disease progression [10, 11] and highly active antiretroviral therapy (HAART) is associated with a lower level of CD4+ T cell apoptosis in HIV-1-infected patients [1214].

In HIV-infected persons, both infected and uninfected cells undergo accelerated apoptosis, in vitro and in vivo. Several mechanisms have been proposed to explain these results: (i) direct role of HIV-specific proteins, (ii) activation-induced cell death (AICD), (iii) direct infection of T lymphocytes, (iv) autologous cell-mediated killing of uninfected T cells and (v) dysregulation of cytokine/chemokine production [15]. However, HIV-1-induced apoptosis in bystander uninfected immune cells is likely the key to the depletion of T lymphocytes observed in HIV-1-infected patients since the degree of cell loss largely exceeds the number of infected cells. Furthermore, the vaste majority of T cells undergoing apoptosis in peripheral blood and lymph nodes of HIV patients are uninfected [16, 17]. Using several animal models, such as rhesus macaques infected by SIV or highly pathogenic SIV/HIV chimeric viruses and human PBL-transplanted nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice, massive apoptosis was predominantly observed in uninfected CD4+ T cells present in lymph nodes, thymus or spleen [1820].

Several HIV-1 proteins, such as HIV envelope glycoproteins (Env), Tat, Vpr, Nef, Vpu and the protease can induce T cell apoptosis. No one has a full grasp of the real importance of this process in vivo, but cumulative data demonstrate a major role of Env in cell death of uninfected lymphocytes [2124].

These two global mechanisms leading to T cell loss in HIV disease are not mutually exclusive. Over the past several years, many data were obtained on signaling induced after Env binding to its receptors leading to T cell apoptosis. The purpose of this review is thus to summarize recent information on apoptotic pathways shown to be activated by Env in uninfected cells and to highlight the pathological consequences of this cell death. Novel avenues for clinical managements of AIDS based on this research are also discussed.

HIV envelope glycoproteins as inducers of apoptosis

The mature HIV-1 envelope glycoproteins are composed of gp120, the exterior envelope glycoprotein, and gp41, the transmembrane glycoprotein assembled as trimer by non covalent interactions. Obviously, the viral envelope can be considered as an extracellular ligand. Consequently, binding of HIV-1 Env gp120/gp41 to its receptors constitutes the primary interface between viruses and T cells and this event is likely able to modulate T cell signaling.

In most cases, to enter a target cell, HIV-1 must bind two molecules on the surface of target cells. gp120 first interacts with CD4, which triggers conformational changes leading to increased exposure of the gp120 V3 loop that is then able to bind to several coreceptors that determine the tropism of the virus for particular cell types [25]. CCR5 and CXCR4 are the main HIV coreceptors [2628] but several other members of the chemokine receptor family, such as CCR1, CCR2b, CCR3, CCR4, CCR8, CX3CR1, BOB/GPR15, Bonzo/CXCR6, GPR1, US28 and APJ can also be used as coreceptors for viral entry [2934]. These events trigger the formation of a coiled-coil structure in the gp41 ectodomain that places the hydrophobic aminoterminal region of gp41 in close proximity to the cellular membrane, thereby inducing cell fusion [35].

Transmissible, macrophage-tropic HIV-1 strains, named R5, use CCR5 as a coreceptor. As the disease progresses, in many individuals, viruses emerge that have T-tropic characteristics. These strains are able to use CXCR4 alone or in combination with other coreceptors. The correlation between the clinical outcome and extended viral tropism is still a subject of debate. Indeed, in most cases, disease progression does not seem to correlate directly with the emergence of variants that can use multiple coreceptors [36] but viral adaptation has also been described to follow in vivo HIV-1 disease progression [37]. Evolution of coreceptor use is a continuous process that may lead to change in the way coreceptors are used, with the potential of altering signaling at that receptor and sensitivity to inhibition by chemokines, neutralizing antibodies or drugs that target coreceptor binding. HIV-1 Env interaction with each of these receptors (CD4 and a coreceptor) can thus dictate the molecular mechanisms transducing apoptosis in uninfected T cells.

Depending on Env presentation and on the complexity of target cell contact, the mechanisms leading to cell death may also be different. Indeed, soluble Env, secreted from infected cells, Env expressed on virions or at the cell surface of infected cells, are able to induce apoptosis of uninfected T cells. Soluble Env resulting from shedding of the surfaces of viral particles or infected cells can be considered as a ligand of CD4 and coreceptor molecules and acts as a signaling molecule through these receptors. Noninfectious virions provide a powerful tool to dissect mechanisms activated through HIV particles without viral replication. Finally, infected cells expressing Env at their surface can interact with uninfected T cells presenting CD4 and coreceptor molecules and can elicit several events, (i) an apoptotic signaling through one of these receptors, (ii) an hemifusion event leading to target cell death or (iii) syncytium formation (Fig. 1).

Figure 1

Schematic diagram of Env-induced CD4+ T cell apoptosis

It is worth noting that apoptosis is seen in both CD4+ and CD8+ lymphocytes from peripheral blood [10, 11, 38, 39] and correlates with disease progression.

Furthermore, Env of HIV-2 (gp105/gp36) generally binds to the same receptors as HIV-1, even if several primary HIV-2 strains can infect CCR5+ or CXCR4+ cell lines without the requirement of CD4 interaction in vitro [40]. However, T cell decline and clinical progression to AIDS occur at a slower rate [41, 42]. HIV-2 Env has much more marked inhibitory properties on TCR-mediated lymphoproliferative responses that HIV-1 Env does, without overinducing apoptosis, explaining the model of "attenuated disease" [43].

Env-mediated apoptosis of bystander CD4+ T cells

Apoptosis of single cells

Signaling through CD4

The CD4 molecule is a transmembrane glycoprotein which is essential for the helper functions of mammalian T cells since it acts as a receptor for major histocompatibility complex (MHC) class II. In lymphocytes, apoptosis is an important physiological mechanism that regulates the capacity of immune responses to maintain tolerance to self-antigens. Two apoptotic pathways have been described as operative in T lymphocytes: activation-induced and spontaneous or passive cell death. AICD occurs as a result of repeated antigenic stimulation and is mediated by the interaction of the cell death receptor Fas and its ligand (Fas-L), expressed either on the same cells or on neighbouring activated T cells. The role of this Fas/FasL apoptotic pathway in HIV disease has been previously reviewed by D. Kaplan and S. Sieg [44]. The proportion of Fas-expressing T cells in patients increases with disease progression, and peripheral blood CD4+ T lymphocytes from HIV-infected individuals undergo apoptosis in response to stimulation through Fas antigen at a much higher frequency than from uninfected controls [4553]. In the same way, high levels of Fas-susceptibility found in peripheral CD4+ T cells before HAART are significantly reduced after treatment, coinciding with a decrease in viral load and an increase in peripheral CD4+ T lymphocytes counts.

Cross-ligation of CD4 molecules prior to T cell receptor (TCR) stimulation triggers an up-regulation of Fas on purified T cells and expression of FasL upon antigen-, mitogen- and CD3 stimulation, rendering the T cells susceptible to Fas-mediated apoptosis [54]. It is quite likely that CD4+ uninfected T cells from HIV-infected patients are continuously undergoing CD4 cross-linking through interaction with virions or via Env expressed at the surface of infected cells. This phenomenon occurs essentially in lymphoid tissue which is a major reservoir of viral infection in HIV disease and a primary site of antigen presentation and lymphocyte activation. Indeed, apoptosis is predominantly seen in uninfected bystander cells present in HIV-1 infected individual lymph nodes [17]. When these CD4-cross-linked uninfected T cells encounter antigen-presenting cells in the local environment, they receive stimulatory signals through the TCR, leading to increased apoptosis [54, 55]. This supports the concept that circulating T lymphocytes from HIV-infected patients are in an enhanced state of immune activation, which, in fact, may translate into the observed increased levels of ex vivo spontaneous T cell apoptosis, activation-induced T cell apoptosis and T cell susceptibility to Fas-dependent apoptosis [13, 52, 5659].

Another mechanism for depletion of bystander T cells, observed in the lymph nodes of AIDS patients, was suggested when it was discovered that about one-half of the resting CD4+ lymphocytes that were pre-exposed to HIV (but not infected) were induced into apoptosis following signaling through receptors necessary for homing to lymph nodes [60].

However, the possible involvement of the Fas/FasL pathway in activation-induced cell death of T lymphocytes from HIV-1-infected persons has not produced a clear consensus [6164]. These discrepancies may reflect different stages of disease, level of peripheral blood T cell activation or mode of T cell stimulation (e.g., superantigen or anti-CD3-induced T cell apoptosis).

In addition, tumor necrosis factor (TNF) [58, 65, 66] and TRAIL (DR4 and DR5) receptors [67, 68] may also be involved in deregulated apoptosis during HIV-1 infection.

Besides the fact that CD4 is engaged in T cell activation, direct cross-linking of CD4/HIV gp120 complexes by antibodies can initiate T cell apoptosis using in vitro cellular experiments from transgenic mice expressing human CD4 at the surface of lymphocytes [69, 70].

Identification, in 1996, of G-protein-coupled receptors as HIV coreceptors, has brought a higher level of complexity in signals that can be triggered after HIV-1 Env binding to its target cell. Thus, consequences of Env binding to T cells are multiple, engaging at the same time CD4 and a coreceptor molecule.

Signaling through the coreceptors

The coreceptors are chemokine receptors that belong to the large family of 7-transmembrane domain receptors coupled to heterotrimeric Gi proteins. The misappropriation of chemokine receptor function by HIV Env has important consequences on cell homeostasis. Compared to the natural chemokines, X4 and R5 HIV Env have overlapping but distinct binding sites on chemokine receptors [71, 72]. They are thus able, after interaction with their respective receptors, to transduce some functional responses such as proliferation, differentiation, chemotaxis and proinflammatory cytokine secretion [73, 74] in addition to apoptosis. However, several studies indicate that cell signaling is not needed for HIV-1 Env fusion with the plasma membrane of the target cell [7578].

The main difference between HIV-1 R5 and X4 strains resides in the Env protein sequence, which leads to CCR5 or CXCR4 coreceptor usage, respectively, independently from their common interaction with CD4. CXCR4 and CCR5 stimulation by the corresponding HIV-1 Envs induce several common signaling pathways such as phosphorylation of the tyrosine kinase Pyk2 [79], increased intracellular Ca2+ [73, 80] and c-Jun N-terminal kinase (JNK) activation [81, 82] but differ in their ability to activate the extracellular signal-regulated kinase (ERK) pathway [83]. In the same way, HIV-1 R5 and X4 strains induce differential mechanisms in mediating uninfected T cell death, which could explain the physiopathology of HIV-1 infection.

There is now evidence that Env, either in a soluble or membrane-bound form, mediates death of uninfected bystander CD4+ T cells [17, 22, 66, 84, 85]. Death of uninfected T cells has been shown to occur in lymphoid tissue from HIV-infected patients when contacted by an HIV-infected cell [17]. Soluble gp120 produced within the infected lymphoid tissue could also directly kill or sensitize T cell to subsequent death. Indeed, gp120 at 120–960 ng/mL may exist in lymph nodes of HIV-infected individuals [8688] and 500 ng/mL of soluble gp120 is sufficient to mediate significant T cell death [89].


CXCR4 is a receptor for the chemokine stromal cell-derived factor-1 (SDF-1) [28, 90] and is widely expressed in various hematopoietic cells. SDF-1/CXCR4 regulates pre-B-cell proliferation, myeolopoiesis, cerebellar development and cardiogenesis [9193]. Furthermore, upregulation of CXCR4 that occurs in T cells from lymphoid tissue in HIV-infected patients may favor X4 Env/CXCR4 interactions.

The first experiments indicating that Env-induced death program could be independent of CD4 signaling, and thus coreceptor dependent, were done with human T cell lines in which the cytoplasmic part of CD4 was missing. Indeed, infectious X4 isolates of HIV-1 induce apoptosis of different T cell lines lacking the CD4 cytoplasmic domain and thus unable to transduce a signal through CD4 [94, 95]. In parallel, L. Moutouh and collaborators demonstrated that p56lck signaling is dispensable for HIV-1-mediated apoptosis [63]. Similarly, the capability of SDF-1 and CXCR4 antagonists to block Env-induced cell death underlines the role of CXCR4 in this death signaling [61, 96, 97].

As early as 1998, a consensus has emerged that CXCR4 triggers a death signal in CD4+ T cells after interaction with Env, independently of G-protein signaling [61, 98102]. Using a human embryonic kidney 293(HEK.293) cell line stably cotransfected with CXCR4 and a mutated form of CD4 lacking its cytoplasmic domain, T cell lines and primary umbilical cord blood CD4+ T lymphocytes, we demonstrated that the apoptotic signaling induced in these target cells after contact with cells expressing X4 Env is specifically triggered by CXCR4, dependent of the mitochondrial intrinsic pathway but does not involve activation of the stress- and apoptosis-related mitogen-activated protein kinases (MAPKs) p38 and JNK [96, 98, 103]. Notably, binding of HIV-1 Env to CXCR4 induces mitochondrial transmembrane depolarization, cytochrome c release from the mitochondria to the cytosol and activation of the caspases-9 and -3. Furthermore, Env-induced apoptosis through CXCR4 is Fas independent [61, 64, 100, 101, 103, 104]. However, there is some controversy as to the conformation of gp120 needed to induce cell death. In a majority of cellular models, Env has to be expressed on cells to trigger T cell apoptosis but recombinant gp120 alone or cross-linked with anti-gp120 antibodies was also shown to trigger CD4+ T cell death [61, 105].

Direct implication of caspases in Env-mediated cell death of CXCR4+ cells is still a subject of debate. Berndt and collaborators described no involvement of known caspases in cross-linked recombinant gp120- and anti-CXCR4-induced apoptosis of human peripheral blood lymphocytes [61] and Vlahakis and collaborators reported that CXCR4-dependent cell death is caspase independent on the basis of caspases inhibitors [89]. However, caspase-3 is cleaved in primary T lymphocytes [103, 105] and endothelial cells [106, 107] following binding of HIV-1 Env.

The manner in which Env is presented, the cell population analyzed and the nature of the receptor directly involved in this cell death could be responsible for the discrepancies between these reports. However, multiple experiments, using different cell lines, human primary T cells and human lymphoid cultures ex vivo [108] support the view that Env interaction with CXCR4 on bystander CD4+ T cells triggers apoptosis. These results are consistent with observations made from AIDS patients and explain the high CD4+ T cell depletion that occurs after X4 isolate emergence.


Only about 15 to 30% of the CD4+ T lymphocytes express detectable levels of CCR5 on the cell surface in contrast to CXCR4 which is expressed on nearly all of these T cells [109, 110]. This explains, at least in part, that X4 strains exert a profound cytopathic effect on a much wider range of target cells via their particular capacity to induce bystander apoptosis. However, even if bystander apoptosis is an important characteristic of X4 HIV-1 strains, mediated by binding of X4 Env to CXCR4 on CD4+ T lymphocytes, R5 Env binding to CCR5 expressed on uninfected resting primary T cells and human vascular endothelial cells has also been shown to trigger apoptosis [111, 112]. Stimulation of CCR5 by R5 Env or anti-CCR5 antibody leads to FasL up-regulation, inducing caspase-8 activation in resting primary CD4+ T cells [111]. Yao and collaborators also demonstrated that R5 and X4 Env expressed on simian HIV virus-like particles induce apoptosis through their respective coreceptors expressed on human osteosarcoma (HOS) cells [113]. However, apoptosis of bystander CD4+ T cells observed in human lymphoid tissues ex vivo after infection with R5 viruses was shown to be only a minor mechanism [108].

Apoptosis after cell-to-cell fusion

HIV-1 Env (gp120/gp41) expressed at the surface of infected cells drives cell-to-cell fusion with adjacent uninfected CD4+ T cells [21, 22, 114, 115], which results in formation of multinucleated syncytia [114, 116]. Hemifusion events as well as syncytium formation have been shown to trigger cell apoptosis and thus to participate to the global loss of CD4+ T cells during AIDS.

Role of gp41-mediated hemifusion-like events

Destruction of primary CD4+ T cells can occur by cell-cell interaction in HIV-1 infection in vitro [117]. Furthermore, agents interfering with cell-to-cell fusion, such as the peptide T20 which abolishes a correct gp41 folding after gp120 binding to its receptor molecules and insertion of the gp41 fusion peptide into cell membrane [118], prevent cell death and T cell depletion [117]. Blanco and collaborators recently demonstrated that Env-induced cell death of single CD4+ T cells requires both gp120 and gp41 functions [119].

These data indicate that besides the role of gp120, gp41 could actively participate in the molecular events leading to Env-induced cell death.

Apoptosis of syncytia

Syncytia are not stable over an extended time-period [114, 116] and are not detectable in infected individuals except in brain [120] and tonsils [121] but can amplify the global apoptotic signaling [122].

Syncytium formation leads to apoptosis mediated by the intrinsic mitochondrial pathway [123] and involves a precise sequence of events: (i) activation of the mammalian target of rapamycin mTOR, (ii) mammalian target of rapamycin (mTOR)-mediated phosphorylation of p53 on serine 15, (iii) p53-dependent upregulation of Bax expression, (iv) Bax-mediated permeabilization of mitochondrial membranes with reduction of the mitochondrial transmembrane potential and release of proapoptotic mitochondrial proteins such as apoptosis-inducing factor AIF and cytochrome c and (v) activation of caspase-3 and nuclear chromatin condensation [124, 125].

Env-mediated apoptosis of CD8+ T lymphocytes

HIV infection is characterized by a persistent immune activation and a concomitant decline in both CD4+ and CD8+ naïve lymphocytes in the early stages of the disease [126]. In the later stages, both CD4+ and CD8+ memory T cells decline at similar rates. Notably, apoptosis is seen in peripheral blood CD4+ and CD8+ T lymphocytes of HIV-infected patients [10, 11, 38, 39] as well as in CD4+ and CD8+ T cells present in lymph nodes of HIV-infected persons [127]. The degree of apoptosis observed in these cells is significantly higher in infected patients than in uninfected individuals [11] and CD8+ as well as CD4+ peripheral blood T cells from HIV-infected persons are susceptible to Fas- and activation-induced apoptosis [58]. Furthermore, this cell death correlates with disease progression and severity [49, 52]. These data suggest that survival and differentiation of HIV-specific CD8+ T cells may be compromised by Fas apoptosis induced by FasL-expressing HIV-infected cells [128]. In addition to direct CD8+ T cell death mediated by the death receptor Fas, CD4 cross-linking by Env interaction in uninfected CD4+ lymphocytes prior to TCR stimulation leads to the generation of FasL-expressing CD4+ T cells that can trigger CD8+ T cell apoptosis [54].

In addition to Fas sensitivity, CD8+ T lymphocytes from HIV-infected patients are susceptible to proapoptotic signaling through both tumor necrosis factor receptor TNFRI and TNFRII, and this is associated with expression of caspase-8 and -3 and lack of physiological protection by Bcl-2 [67]. IL-15 induces both Bcl-2 and Bcl-xL expression in HIV-specific and total CD8+ T cells, and this phenomenon is correlated with apoptosis inhibition and increased cell survival. Thus, reduced Bcl-2 and Bcl-xL expression found in HIV-specific CD8+ T cells may play an important role in the increased sensitivity to apoptosis [129]. Furthermore, Vlahakis and collaborators demonstrated that CXCR4 activation by X4 Env induces a caspase-independent death of uninfected CD8+ T lymphocytes [89]. One mechanism by which CD8+ T cells undergo apoptosis in HIV disease is dependent upon macrophages [130]. The data indicate that ligation of CXCR4 increased membrane bound TNF on macrophages and TNFRII on CD8+ T cells, and that interaction between TNF and TNFRII triggers CD8+ lymphocyte apoptosis. HIV-1 X4 Env expressed at the surface of conformationally authentic noninfectious virions is also able to trigger apoptosis of CD8+ T lymphocytes [131]. Inhibition of CD4+ and CD8+ T cell apoptosis was observed in HIV patients undergoing potent antiretroviral therapy. Recently, Grelli and collaborators demonstrated that inhibition of apoptotic CD8+ T cells rather than CD4+ T cells are correlated with CD4+ T cell increase during therapy [132], underlying the role of CD8+ T cell apoptosis in disease progression.

CD8+ T cells are known to be essential in controlling HIV infection. Apoptosis of either HIV-specific or total CD8+ T lymphocytes can thus contribute to impair the global immune response against HIV. In addition to HAART, IL-15 could be used as an immunorestorative agent to boost immunity against HIV and to inhibit HIV-induced apoptosis of T cells in HIV patients [133135].

Complications of HIV infection due to Env-induced apoptosis

Besides pathological complications due to opportunistic pathogens, several disorders are direct consequences of HIV infection. Here are described complications that involve Env-mediated apoptosis. Indeed, different in vivo cell types are able to express a coreceptor and/or CD4 and are thus susceptible to Env-mediated apoptosis.

HIV-1-mediated neurotoxicity

HIV-1 Env has been proposed as the major etiologic agent for neuronal damage, mediating both direct and indirect effects on the central nervous system (CNS). Indeed, gp120 has been revealed in the central nervous system of AIDS patients [136] and in the brain of patients with HIV encephalitis and dementia [137]. There is also evidence that gp120 can cross the blood-brain barrier [138]. Furthermore, chemokine receptors have been identified in macrophages/microglia, astrocytes and neurones [139].

HIV-1-associated dementia (HAD) is a common complication of the viral infection late stages affecting nearly 20% and 50% of infected adults and children respectively. In addition to indirect neuronal injury triggered by neurotoxic molecules released from HIV-infected or -activated macrophages and microglia [140144], HIV Env directly triggers apoptosis of both primary rodent and human neurons [81, 145150] and astrocytes [151153] and is probably a cause of CNS injury in AIDS [81, 154158] even if neuronal cells are not productively infected by HIV-1. A direct role of HIV-1 coreceptors is also possible since association between HIV-1 gp120 and CCR5 or CXCR4 expressed in human neurons is CD4 independent [102, 159, 160].

Two major features now emerge from AIDS neurotoxicity studies. First, chemokine receptors are involved in apoptosis of neuronal cells, and second, HIV-1 Env is the major determinant of the HIV-dependent neurodegenerative mechanisms [150, 154, 161]. Understanding the precise role of CXCR4 and other chemokine receptors in HIV-1 neuropathogenesis will help to advance the development of new therapeutic strategies for the prevention and treatment of neurologic disorders associated with HIV-1 infection.

Other complications of HIV-1 infection

HIV-associated cardiomyopathy

Annual incidence of HIV-associated cardiomyopathy is estimated to be 15.9 cases per 1,000 asymptomatic Italian HIV-1-positive patients [162] and leads to a high cardiovascular morbidity and mortality in young and middle-aged adults. Infected hearts show a strong expression of gp120 without productive infection of cardiomyocytes. Twu and collaborators demonstrated in vitro that gp120 induces cardiomyocyte apoptosis by a mitochondrion-controlled pathway and in vivo that death receptor ligands from macrophages are a major cause of apoptosis and that the apoptotic signaling may occur through chemokine receptors [163].

HIV-associated nephropathy

HIV-associated nephropathy (HIVAN) is accompanied by tubular cell proliferation, apoptosis and microcystic dilatation. Through murine and human studies, it is now clear that HIVAN is caused by a direct effect of HIV-1 infection of renal cells and that the virus actively replicates in renal cells [164, 165]. In particular, gp120 induces apoptosis of tubular epithelial cell through p38-MAPK phosphorylation [166]. Furthermore, dysfunction and/or damage of mesangial cells that are susceptible to HIV/SIV strains using GPR1 as coreceptor is thought to be involved in the development of HIV-associated HIVAN [34]. Its remains to investigate whether the interaction of these cells with specific HIV-1 strains through GPR1 plays a significant role in the development of HIVAN.

HIV-mediated hepatocyte death

Liver dysfunction causes significant morbidity among HIV-infected individuals. End-stage liver disease is the most frequent cause of death among HIV-infected hospitalized patients [167]. Although the cause of liver injury in HIV-infected individuals is multifactorial, Vlahakis and collaborators established that HIV-1 X4 Env and the entire virion induce apoptosis of human hepatocytes via CXCR4 [168].


Apoptosis of uninfected CD4+ T lymphocytes is closely linked to activation of the immune system and change in coreceptor usage. One hypothesis might be that, at the first stages of the disease, Env binds to the CD4 and CCR5 molecules, triggering chronic and continuous activation of the immune system that induces a Fas-dependent CD4+ T cell apoptosis upon mobilization of the T cell receptor and antigen. During the progression toward AIDS, X4 strains emerge and their higher pathogenicity may derive from the fact that CXCR4 is able to activate either directly or indirectly a Fas-independent apoptotic signaling pathway, accelerating the immune destruction observed at late stages of AIDS. Furthermore, CXCR4 is widely expressed on immune cells, still increasing the cytopathogenicity of X4 strains. Treatment of HIV-infected patients with protease inhibitors leads to a decrease in CD4+ T cell apoptosis, inducing an increase in CD4+ T cell number and a decrease in viral loads, resulting in clinical improvement. Therapies that block or decrease bystander death could thus have significant clinical benefit. Several interleukins, IL-2, IL-7 and IL-15 could also be used for therapeutic intervention. IL-15, in particular, because of its anti-apoptotic properties and its role in enhancing survival and function of CD8+ T cells, can be an immunorestorative agent in HIV treatment. Finally, as X4 strains are the most pathogenic ones, inducing massive apoptosis of bystander T cells, CXCR4 antagonists would improve clinical AIDS chemotherapy in suppressing Env binding to CXCR4 and X4 HIV-1 entry into target cells. In the same way, Env-binding agents such as plant lectins and glycopeptide antibiotics seem also worthy of further preclinical development. Novel approaches focusing on apoptosis of bystander T cells are required to maintain the homeostatic states of the immune cell populations.



activation-induced cell death


apoptosis-inducing factor


central nervous system


HIV envelope glycoproteins


extracellular signal-regulated kinase


highly active antiretroviral therapy


HIV-associated dementia


human embryonic kidney


HIV-associated nephropathy


human osteosarcoma


c-Jun N-terminal kinase


mitogen-activated protein kinase


major histocompatibility complex


stromal cell-derived factor-1


T cell receptor


tumor necrosis factor


mammalian target of rapamycin.


  1. 1.

    Fauci AS: The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science. 1988, 239: 617-622.

    CAS  PubMed  Google Scholar 

  2. 2.

    McCune JM: The dynamics of CD4+ T-cell depletion in HIV disease. Nature. 2001, 410: 974-979. 10.1038/35073648.

    CAS  PubMed  Google Scholar 

  3. 3.

    Mohri H, Perelson AS, Tung K, Ribeiro RM, Ramratnam B, Markowitz M, Kost R, Hurley A, Weinberger L, Cesar D, Hellerstein MK, Ho DD: Increased turnover of T lymphocytes in HIV-1 infection and its reduction by antiretroviral therapy. J Exp Med. 2001, 194: 1277-1287. 10.1084/jem.194.9.1277.

    PubMed Central  CAS  PubMed  Google Scholar 

  4. 4.

    Grossman Z, Meier-Schellersheim M, Sousa AE, Victorino RM, Paul WE: CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause?. Nat Med. 2002, 8: 319-323. 10.1038/nm0402-319.

    CAS  PubMed  Google Scholar 

  5. 5.

    Deeks SG, Walker BD: The immune response to AIDS virus infection: good, bad, or both?. J Clin Invest. 2004, 113: 808-810. 10.1172/JCI200421318.

    PubMed Central  CAS  PubMed  Google Scholar 

  6. 6.

    Silvestri G, Sodora DL, Koup RA, Paiardini M, O'Neil SP, McClure HM, Staprans SI, Feinberg MB: Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity. 2003, 18: 441-452. 10.1016/S1074-7613(03)00060-8.

    CAS  PubMed  Google Scholar 

  7. 7.

    Sousa AE, Carneiro J, Meier-Schellersheim M, Grossman Z, Victorino RM: CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J Immunol. 2002, 169: 3400-3406.

    CAS  PubMed  Google Scholar 

  8. 8.

    Ameisen JC, Capron A: Cell dysfunction and depletion in AIDS: the programmed cell death hypotheses. Immunol Today. 1991, 12: 102-105.

    CAS  PubMed  Google Scholar 

  9. 9.

    Terai C, Kornbluth RS, Pauza CD, Richman DD, Carson DA: Apoptosis as a mechanism of cell death in cultured T lymphoblasts acutely infected with HIV-1. J Clin Invest. 1991, 87: 1710-1715.

    PubMed Central  CAS  PubMed  Google Scholar 

  10. 10.

    Cotton MF, Ikle DN, Rapaport EL, Marschner S, Tseng PO, Kurrle R, Finkel TH: Apoptosis of CD4+ and CD8+ T cells isolated immediately ex vivo correlates with disease severity in human immunodeficiency virus type 1 infection. Pediatr Res. 1997, 42: 656-664.

    CAS  PubMed  Google Scholar 

  11. 11.

    Gougeon ML, Lecoeur H, Dulioust A, Enouf MG, Crouvoiser M, Goujard C, Debord T, Montagnier L: Programmed cell death in peripheral lymphocytes from HIV-infected persons: increased susceptibility to apoptosis of CD4 and CD8 T cells correlates with lymphocyte activation and with disease progression. J Immunol. 1996, 156: 3509-3520.

    CAS  PubMed  Google Scholar 

  12. 12.

    Badley AD, Dockrell DH, Algeciras A, Ziesmer S, Landay A, Lederman MM, Connick E, Kessler H, Kuritzkes D, Lynch DH, Roche P, Yagita H, Paya CV: In vivo analysis of Fas/FasL interactions in HIV-infected patients. J Clin Invest. 1998, 102: 79-87.

    PubMed Central  CAS  PubMed  Google Scholar 

  13. 13.

    Badley AD, Parato K, Cameron DW, Kravcik S, Phenix BN, Ashby D, Kumar A, Lynch DH, Tschopp J, Angel JB: Dynamic correlation of apoptosis and immune activation during treatment of HIV infection. Cell Death Differ. 1999, 6: 420-432. 10.1038/sj.cdd.4400509.

    CAS  PubMed  Google Scholar 

  14. 14.

    Bohler T, Walcher J, Holzl-Wenig G, Geiss M, Buchholz B, Linde R, Debatin KM: Early effects of antiretroviral combination therapy on activation, apoptosis and regeneration of T cells in HIV-1-infected children and adolescents. Aids. 1999, 13: 779-789. 10.1097/00002030-199905070-00006.

    CAS  PubMed  Google Scholar 

  15. 15.

    Phenix BN, Badley AD: Influence of mitochondrial control of apoptosis on the pathogenesis, complications and treatment of HIV infection. Biochimie. 2002, 84: 251-264. 10.1016/S0300-9084(02)01378-0.

    CAS  PubMed  Google Scholar 

  16. 16.

    Debatin KM, Fahrig-Faissner A, Enenkel-Stoodt S, Kreuz W, Benner A, Krammer PH: High expression of APO-1 (CD95) on T lymphocytes from human immunodeficiency virus-1-infected children. Blood. 1994, 83: 3101-3103.

    CAS  PubMed  Google Scholar 

  17. 17.

    Finkel TH, Tudor-Williams G, Banda NK, Cotton MF, Curiel T, Monks C, Baba TW, Ruprecht RM, Kupfer A: Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med. 1995, 1: 129-134.

    CAS  PubMed  Google Scholar 

  18. 18.

    Igarashi T, Brown CR, Byrum RA, Nishimura Y, Endo Y, Plishka RJ, Buckler C, Buckler-White A, Miller G, Hirsch VM, Martin MA: Rapid and irreversible CD4+ T-cell depletion induced by the highly pathogenic simian/human immunodeficiency virus SHIV(DH12R) is systemic and synchronous. J Virol. 2002, 76: 379-391. 10.1128/JVI.76.1.379-391.2002.

    PubMed Central  CAS  PubMed  Google Scholar 

  19. 19.

    Miura Y, Misawa N, Maeda N, Inagaki Y, Tanaka Y, Ito M., Kayagaki N, Yamamoto N, Yagita H, Mizusawa H, Koyanagi Y: Critical contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to apoptosis of human CD4+ T cells in HIV-1-infected hu-PBL-NOD-SCID mice. J Exp Med. 2001, 193: 651-660. 10.1084/jem.193.5.651.

    PubMed Central  CAS  PubMed  Google Scholar 

  20. 20.

    Monceaux V, Estaquier J, Fevrier M, Cumont MC, Riviere Y, Aubertin AM, Ameisen JC, Hurtrel B: Extensive apoptosis in lymphoid organs during primary SIV infection predicts rapid progression towards AIDS. Aids. 2003, 17: 1585-1596. 10.1097/00002030-200307250-00002.

    PubMed  Google Scholar 

  21. 21.

    Heinkelein M, Sopper S, Jassoy C: Contact of human immunodeficiency virus type 1-infected and uninfected CD4+ T lymphocytes is highly cytolytic for both cells. J Virol. 1995, 69: 6925-6931.

    PubMed Central  CAS  PubMed  Google Scholar 

  22. 22.

    Laurent-Crawford AG, Krust B, Riviere Y, Desgranges C, Muller S, Kieny MP, Dauguet C, Hovanessian AG: Membrane expression of HIV envelope glycoproteins triggers apoptosis in CD4 cells. AIDS Res Hum Retroviruses. 1993, 9: 761-773.

    CAS  PubMed  Google Scholar 

  23. 23.

    Ohnimus H, Heinkelein M, Jassoy C: Apoptotic cell death upon contact of CD4+ T lymphocytes with HIV glycoprotein-expressing cells is mediated by caspases but bypasses CD95 (Fas/Apo-1) and TNF receptor 1. J Immunol. 1997, 159: 5246-5252.

    CAS  PubMed  Google Scholar 

  24. 24.

    Roshal M, Zhu Y, Planelles V: Apoptosis in AIDS. Apoptosis. 2001, 6: 103-116. 10.1023/A:1009636530839.

    CAS  PubMed  Google Scholar 

  25. 25.

    Berger EA: HIV entry and tropism: the chemokine receptor connection. Aids. 1997, 11 (Suppl A): S3-16.

    PubMed  Google Scholar 

  26. 26.

    Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, Berger EA: CC-CKR5: a RANTES, MIP-1α, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996, 272: 1955-1958.

    CAS  PubMed  Google Scholar 

  27. 27.

    Feng Y, Broder CC, Kennedy PE, Berger EA: HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996, 272: 872-877.

    CAS  PubMed  Google Scholar 

  28. 28.

    Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, Sodroski J, Springer TA: The lymphocyte chemoattractant SDF-1 is a ligand for LESTRE/fusin and blocks HIV-1 entry. Nature. 1996, 382: 829-833. 10.1038/382829a0.

    CAS  PubMed  Google Scholar 

  29. 29.

    Deng HK, Unutmaz D, KewalRamani VN, Littman DR: Expression cloning of new receptors used by simian and human immunodeficiency viruses. Nature. 1997, 388: 296-300. 10.1038/40894.

    CAS  PubMed  Google Scholar 

  30. 30.

    Choe H, Farzan M, Sun Y, Sullivan N, Rollins B, Ponath PD, Wu L, Mackay CR, LaRosa G, Newman W, Gerard N, Gerard C, Sodroski J: The β-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell. 1996, 85: 1135-1148. 10.1016/S0092-8674(00)81313-6.

    CAS  PubMed  Google Scholar 

  31. 31.

    Doranz BJ, Rucker J, Yi Y, Smyth RJ, Samson M, Parmentier M, Collman RG, Doms RW: A dual-tropic, primary HIV-1 isolate that uses both fusin and the β-chemokine receptor CKR-5 as entry cofactors. Cell. 1996, 85: 1149-1158. 10.1016/S0092-8674(00)81314-8.

    CAS  PubMed  Google Scholar 

  32. 32.

    Horuk R, Hesselgesser J, Zhou Y, Faulds D, Halks-Miller M, Harvey S, Taub D, Samson M, Parmentier M, Rucker J, Doranz BJ, Doms RW: The CC chemokine I-309 inhibits CCR8-dependent infection by diverse HIV-1 strains. J Biol Chem. 1998, 273: 386-391. 10.1074/jbc.273.1.386.

    CAS  PubMed  Google Scholar 

  33. 33.

    Owen SM, Ellenberger D, Rayfield M, Wiktor S, Michel P, Grieco MH, Gao F, Hahn BH, Lal RB: Genetically divergent strains of human immunodeficiency virus type 2 use multiple coreceptors for viral entry. J Virol. 1998, 72: 5425-5432.

    PubMed Central  CAS  PubMed  Google Scholar 

  34. 34.

    Tokizawa S, Shimizu N, Hui-Yu L, Deyu F, Haraguchi Y, Oite T, Hoshino H: Infection of mesangial cells with HIV and SIV: identification of GPR1 as a coreceptor. Kidney Int. 2000, 58: 607-617. 10.1046/j.1523-1755.2000.00207.x.

    CAS  PubMed  Google Scholar 

  35. 35.

    Weissenhorn W, Dessen A, Harrison SC, Skehel JJ, Wiley DC: Atomic structure of the ectodomain from HIV-1 gp41. Nature. 1997, 387: 426-430. 10.1038/387426a0.

    CAS  PubMed  Google Scholar 

  36. 36.

    Begaud E, Feindirongai G, Versmisse P, Ipero J, Leal J, Germani Y, Morvan J, Fleury H, Muller-Trutwin M, Barre-Sinoussi F, Pancino G: Broad spectrum of coreceptor usage and rapid disease progression in HIV-1-infected individuals from Central African Republic. AIDS Res Hum Retroviruses. 2003, 19: 551-560. 10.1089/088922203322230914.

    CAS  PubMed  Google Scholar 

  37. 37.

    Xiao L, Rudolph DL, Owen SM, Spira TJ, Lal RB: Adaptation to promiscuous usage of CC and CXC-chemokine coreceptors in vivo correlates with HIV-1 disease progression. Aids. 1998, 12: F137-143. 10.1097/00002030-199813000-00001.

    CAS  PubMed  Google Scholar 

  38. 38.

    Carbonari M, Cibati M, Pesce AM, Sbarigia D, Grossi P, D'Offizi G, Luzi G, Fiorilli M: Frequency of provirus-bearing CD4+ cells in HIV type 1 infection correlates with extent of in vitro apoptosis of CD8+ but not of CD4+ cells. AIDS Res Hum Retroviruses. 1995, 11: 789-794.

    CAS  PubMed  Google Scholar 

  39. 39.

    Bofill M, Gombert W, Borthwick NJ, Akbar AN, McLaughlin JE, Lee CA, Johnson MA, Pinching AJ, Janossy G: Presence of CD3+CD8+Bcl-2(low) lymphocytes undergoing apoptosis and activated macrophages in lymph nodes of HIV-1+ patients. Am J Pathol. 1995, 146: 1542-1555.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. 40.

    Reeves JD, Hibbitts S, Simmons G, McKnight A, Azevedo-Pereira JM, Moniz-Pereira J, Clapham PR: Primary human immunodeficiency virus type 2 (HIV-2) isolates infect CD4-negative cells via CCR5 and CXCR4: comparison with HIV-1 and simian immunodeficiency virus and relevance to cell tropism in vivo. J Virol. 1999, 73: 7795-7804.

    PubMed Central  CAS  PubMed  Google Scholar 

  41. 41.

    Jaffar S, Wilkins A, Ngom PT, Sabally S, Corrah T, Bangali JE, Rolfe M, Whittle HC: Rate of decline of percentage CD4+ cells is faster in HIV-1 than in HIV-2 infection. J Acquir Immune Defic Syndr Hum Retrovirol. 1997, 16: 327-332.

    CAS  PubMed  Google Scholar 

  42. 42.

    Marlink R, Kanki P, Thior I, Travers K, Eisen G, Siby T, Traore I, Hsieh CC, Dia MC, Gueye EH: Reduced rate of disease development after HIV-2 infection as compared to HIV-1. Science. 1994, 265: 1587-1590.

    CAS  PubMed  Google Scholar 

  43. 43.

    Cavaleiro R, Sousa AE, Loureiro A, Victorino RM: Marked immunosuppressive effects of the HIV-2 envelope protein in spite of the lower HIV-2 pathogenicity. Aids. 2000, 14: 2679-2686. 10.1097/00002030-200012010-00007.

    CAS  PubMed  Google Scholar 

  44. 44.

    Kaplan D, Sieg S: Role of the Fas/Fas ligand apoptotic pathway in human immunodeficiency virus type 1 disease. J Virol. 1998, 72: 6279-6282.

    PubMed Central  CAS  PubMed  Google Scholar 

  45. 45.

    Aries SP, Schaaf B, Muller C, Dennin RH, Dalhoff K: Fas (CD95) expression on CD4+ T cells from HIV-infected patients increases with disease progression. J Mol Med. 1995, 73: 591-593.

    CAS  PubMed  Google Scholar 

  46. 46.

    Baumler CB, Bohler T, Herr I, Benner A, Krammer PH, Debatin KM: Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children. Blood. 1996, 88: 1741-1746.

    CAS  PubMed  Google Scholar 

  47. 47.

    Bohler T, Baumler C, Herr I, Groll A, Kurz M, Debatin KM: Activation of the CD95 system increases with disease progression in human immunodeficiency virus type 1-infected children and adolescents. Pediatr Infect Dis J. 1997, 16: 754-759. 10.1097/00006454-199708000-00005.

    CAS  PubMed  Google Scholar 

  48. 48.

    Dockrell DH, Badley AD, Algeciras-Schimnich A, Simpson M, Schut R, Lynch DH, Paya CV: Activation-induced CD4+ T cell death in HIV-positive individuals correlates with Fas susceptibility, CD4+ T cell count, and HIV plasma viral copy number. AIDS Res Hum Retroviruses. 1999, 15: 1509-1518. 10.1089/088922299309793.

    CAS  PubMed  Google Scholar 

  49. 49.

    Estaquier J, Idziorek T, Zou W, Emilie D, Farber CM, Bourez JM, Ameisen JC: T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)-mediated apoptosis of CD4+ T cells from human immunodeficiency virus-infected persons. J Exp Med. 1995, 182: 1759-1767. 10.1084/jem.182.6.1759.

    CAS  PubMed  Google Scholar 

  50. 50.

    Gehri R, Hahn S, Rothen M, Steuerwald M, Nuesch R, Erb P: The Fas receptor in HIV infection: expression on peripheral blood lymphocytes and role in the depletion of T cells. Aids. 1996, 10: 9-16.

    CAS  PubMed  Google Scholar 

  51. 51.

    Hosaka N, Oyaizu N, Kaplan MH, Yagita H, Pahwa S: Membrane and soluble forms of Fas (CD95) and Fas ligand in peripheral blood mononuclear cells and in plasma from human immunodeficiency virus-infected persons. J Infect Dis. 1998, 178: 1030-1039.

    CAS  PubMed  Google Scholar 

  52. 52.

    Katsikis PD, Wunderlich ES, Smith CA, Herzenberg LA: Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals. J Exp Med. 1995, 181: 2029-2036. 10.1084/jem.181.6.2029.

    CAS  PubMed  Google Scholar 

  53. 53.

    Silvestris F, Cafforio P, Frassanito MA, Tucci M, Romito A, Nagata S, Dammacco F: Overexpression of Fas antigen on T cells in advanced HIV-1 infection: differential ligation constantly induces apoptosis. Aids. 1996, 10: 131-141.

    CAS  PubMed  Google Scholar 

  54. 54.

    Tateyama M, Oyaizu N, McCloskey TW, Than S, Pahwa S: CD4 T lymphocytes are primed to express Fas ligand by CD4 cross-linking and to contribute to CD8 T-cell apoptosis via Fas/FasL death signaling pathway. Blood. 2000, 96: 195-202.

    CAS  PubMed  Google Scholar 

  55. 55.

    Cottrez F, Manca F, Dalgleish AG, Arenzana-Seisdedos F, Capron A, Groux H: Priming of human CD4+ antigen-specific T cells to undergo apoptosis by HIV-infected monocytes. A two-step mechanism involving the gp120 molecule. J Clin Invest. 1997, 99: 257-266.

    PubMed Central  CAS  PubMed  Google Scholar 

  56. 56.

    Badley AD, Dockrell D, Paya CV: Apoptosis in AIDS. Adv Pharmacol. 1997, 41: 271-294.

    CAS  PubMed  Google Scholar 

  57. 57.

    Bottarel F, Feito MJ, Bragardo M, Bonissoni S, Buonfiglio D, DeFranco S, Malavasi F, Bensi T, Ramenghi U, Dianzani U: The cell death-inducing ability of glycoprotein 120 from different HIV strains correlates with their ability to induce CD4 lateral association with CD95 on CD4+ T cells. AIDS Res Hum Retroviruses. 1999, 15: 1255-1263. 10.1089/088922299310151.

    CAS  PubMed  Google Scholar 

  58. 58.

    Katsikis P, Garcia-Ojeda M, Torres-Roca J, Tijoe I, Smith C, Herzenberg L: Interleukin-1β converting enzyme-like protease involvement in Fas-induced peripheral blood T cell apoptosis in HIV infection. TNF-related apoptosis-inducing ligand can mediate activation-induced T cell death in HIV infection. J Exp Med. 1997, 186: 1365-1372. 10.1084/jem.186.8.1365.

    PubMed Central  CAS  PubMed  Google Scholar 

  59. 59.

    Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X: Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science. 1997, 275: 1129-1132. 10.1126/science.275.5303.1129.

    CAS  PubMed  Google Scholar 

  60. 60.

    Wang L, Chen JJ, Gelman BB, Konig R, Cloyd MW: A novel mechanism of CD4 lymphocyte depletion involves effects of HIV on resting lymphocytes: induction of lymph node homing and apoptosis upon secondary signaling through homing receptors. J Immunol. 1999, 162: 268-276.

    CAS  PubMed  Google Scholar 

  61. 61.

    Berndt C, Mopps B, Angermuller S, Gierschik P, Krammer PH: CXCR4 and CD4 mediate a rapid CD95-independent cell death in CD4+ T cells. Proc Natl Acad Sci USA. 1998, 95: 12556-12561. 10.1073/pnas.95.21.12556.

    PubMed Central  CAS  PubMed  Google Scholar 

  62. 62.

    Gandhi RT, Chen BK, Straus SE, Dale JK, Lenardo MJ, Baltimore D: HIV-1 directly kills CD4+ T cells by a Fas-independent mechanism. J Exp Med. 1998, 187: 1113-1122. 10.1084/jem.187.7.1113.

    PubMed Central  CAS  PubMed  Google Scholar 

  63. 63.

    Moutouh L, Estaquier J, Richman DD, Corbeil J: Molecular and cellular analysis of human immunodeficiency virus-induced apoptosis in lymphoblastoid T-cell-line-expressing wild-type and mutated CD4 receptors. J Virol. 1998, 72: 8061-8072.

    PubMed Central  CAS  PubMed  Google Scholar 

  64. 64.

    Noraz N, Gozlan J, Corbeil J, Brunner T, Spector SA: HIV-induced apoptosis of activated primary CD4+ T lymphocytes is not mediated by Fas-Fas ligand. Aids. 1997, 11: 1671-1680. 10.1097/00002030-199714000-00003.

    CAS  PubMed  Google Scholar 

  65. 65.

    Badley AD, Dockrell DH, Algeciras A, Ziesmer S, Landay A, Lederman MM, Connick E, Kessler H, Kuritzkes D, Lynch DH, Roche P, Yagita H, Paya CV: Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor. J Exp Med. 1997, 185: 55-64. 10.1084/jem.185.1.55.

    PubMed Central  CAS  PubMed  Google Scholar 

  66. 66.

    Algeciras A, Dockrell DH, Lynch DH, Paya CV: CD4 regulates susceptibility to Fas ligand- and tumor necrosis factor-mediated apoptosis. J Exp Med. 1998, 187: 711-720. 10.1084/jem.187.5.711.

    PubMed Central  CAS  PubMed  Google Scholar 

  67. 67.

    de Oliveira Pinto LM, Garcia S, Lecoeur H, Rapp C, Gougeon ML: Increased sensitivity of T lymphocytes to tumor necrosis factor receptor 1 (TNFR1)- and TNFR2-mediated apoptosis in HIV infection: relation to expression of Bcl-2 and active caspase-8 and caspase-3. Blood. 2002, 99: 1666-1675. 10.1182/blood.V99.5.1666.

    CAS  PubMed  Google Scholar 

  68. 68.

    Jeremias I, Herr I, Boehler T, Debatin KM: TRAIL/Apo-2-ligand-induced apoptosis in human T cells. Eur J Immunol. 1998, 28: 143-152. 10.1002/(SICI)1521-4141(199801)28:01<143::AID-IMMU143>3.0.CO;2-3.

    CAS  PubMed  Google Scholar 

  69. 69.

    Kang Y, Melo EF, Scott DW: An ongoing immune response to HIV envelope gp120 in human CD4-transgenic mice contributes to T cell decline upon intravenous administration of gp120. Eur J Immunol. 1998, 28: 2253-2264. 10.1002/(SICI)1521-4141(199808)28:08<2253::AID-IMMU2253>3.0.CO;2-2.

    CAS  PubMed  Google Scholar 

  70. 70.

    Finco O, Nuti S, De Magistris MT, Mangiavacchi L, Aiuti A, Forte P, Fantoni A, van der Putten H, Abrignani S: Induction of CD4+ T cell depletion in mice doubly transgenic for HIV gp120 and human CD4. Eur J Immunol. 1997, 27: 1319-1324.

    CAS  PubMed  Google Scholar 

  71. 71.

    Lee B, Sharron M, Blanpain C, Doranz BJ, Vakili J, Setoh P, Berg E, Liu G, Guy HR, Durell SR, Parmentier M, Chang CN, Price K, Tsang M, Doms RW: Epitope mapping of CCR5 reveals multiple conformational states and distinct but overlapping structures involved in chemokine and coreceptor function. J Biol Chem. 1999, 274: 9617-9626. 10.1074/jbc.274.14.9617.

    CAS  PubMed  Google Scholar 

  72. 72.

    Doranz BJ, Orsini MJ, Turner JD, Hoffman TL, Berson JF, Hoxie JA, Peiper C, Brass LF, Doms RW: Identification of CXCR4 domains that support coreceptor and chemokine receptor functions. J Virol. 1999, 73: 2752-2761.

    PubMed Central  CAS  PubMed  Google Scholar 

  73. 73.

    Weissman D, Rabin RL, Arthos J, Rubbert A, Dybul M, Swofford R, Venkatesan S, Farber JM, Fauci AS: Macrophage-tropic HIV and SIV envelope proteins induce a signal through the CCR5 chemokine receptor. Nature. 1997, 389: 981-985. 10.1038/40173.

    CAS  PubMed  Google Scholar 

  74. 74.

    Misse D, Cerutti M, Noraz N, Jourdan P, Favero J, Devauchelle G, Yssel H, Taylor N, Veas F: A CD4-independent interaction of human immunodeficiency virus-1 gp120 with CXCR4 induces their cointernalization, cell signaling, and T-cell chemotaxis. Blood. 1999, 93: 2454-2462.

    CAS  PubMed  Google Scholar 

  75. 75.

    Atchison RE, Gosling J, Monteclaro FS, Franci C, Digilio L, Charo IF, Goldsmith MA: Multiple extracellular elements of CCR5 and HIV-1 entry: dissociation from response to chemokines. Science. 1996, 274: 1924-1926. 10.1126/science.274.5294.1924.

    CAS  PubMed  Google Scholar 

  76. 76.

    Gosling J, Monteclaro FS, Atchison RE, Arai H, Tsou CL, Goldsmith MA, Charo IF: Molecular uncoupling of C-C chemokine receptor 5-induced chemotaxis and signal transduction from HIV-1 coreceptor activity. Proc Natl Acad Sci U S A. 1997, 94: 5061-5066. 10.1073/pnas.94.10.5061.

    PubMed Central  CAS  PubMed  Google Scholar 

  77. 77.

    Alkhatib G, Ahuja SS, Light D, Mummidi S, Berger EA, Ahuja SK: CC chemokine receptor 5-mediated signaling and HIV-1 Co-receptor activity share common structural determinants. Critical residues in the third extracellular loop support HIV-1 fusion. J Biol Chem. 1997, 272: 19771-19776. 10.1074/jbc.272.32.19771.

    CAS  PubMed  Google Scholar 

  78. 78.

    Farzan M, Choe H, Martin KA, Sun Y, Sidelko M, Mackay CR, Gerard NP, Sodroski J, Gerard C: HIV-1 entry and macrophage inflammatory protein-1beta-mediated signaling are independent functions of the chemokine receptor CCR5. J Biol Chem. 1997, 272: 6854-6857. 10.1074/jbc.272.11.6854.

    CAS  PubMed  Google Scholar 

  79. 79.

    Davis CB, Dikic I, Unutmaz D, Hill CM, Arthos J, Siani MA, Thompson DA, Schlessinger J, Littman DR: Signal transduction due to HIV-1 envelope interactions with chemokine receptors CXCR4 or CCR5. J Exp Med. 1997, 186: 1793-1798. 10.1084/jem.186.10.1793.

    PubMed Central  CAS  PubMed  Google Scholar 

  80. 80.

    Del Corno M, Liu QH, Schols D, de Clercq E, Gessani S, Freedman BD, Collman RG: HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling. Blood. 2001, 98: 2909-2916. 10.1182/blood.V98.10.2909.

    CAS  PubMed  Google Scholar 

  81. 81.

    Lannuzel A, Barnier JV, Hery C, Huynh VT, Guibert B, Gray F, Vincent JD, Tardieu M: Human immunodeficiency virus type 1 and its coat protein gp120 induce apoptosis and activate JNK and ERK mitogen-activated protein kinases in human neurons. Ann Neurol. 1997, 42: 847-856.

    CAS  PubMed  Google Scholar 

  82. 82.

    Popik W, Pitha PM: Early activation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and c-jun n-terminal kinase in response to binding of simian immunodeficiency virus to Jurkat T cells expressing CCR5 receptor. Virology. 1998, 252: 210-217. 10.1006/viro.1998.9466.

    CAS  PubMed  Google Scholar 

  83. 83.

    Popik W, Hesselgesser JE, Pitha PM: Binding of human immunodeficiency virus type 1 to CD4 and CXCR4 receptors differentially regulates expression of inflammatory genes and activates the MEK/ERK signaling pathway. J Virol. 1998, 72: 6406-6413.

    PubMed Central  CAS  PubMed  Google Scholar 

  84. 84.

    Zarling JM, Ledbetter JA, Sias J, Fultz P, Eichberg J, Gjerset G, Moran PA: HIV-infected humans, but not chimpanzees, have circulating cytotoxic T lymphocytes that lyse uninfected CD4+ cells. J Immunol. 1990, 144: 2992-2998.

    CAS  PubMed  Google Scholar 

  85. 85.

    Nardelli B, Gonzalez CJ, Schechter M, Valentine FT: CD4+ blood lymphocytes are rapidly killed in vitro, by contact with autologous human immunodeficiency virus-infected cells. Proc Natl Acad Sci USA. 1995, 92: 7312-7316.

    PubMed Central  CAS  PubMed  Google Scholar 

  86. 86.

    Pantaleo G, Graziosi C, Demarest JF, Butini L, Montroni M, Fox CH, Orentein JM, Kotler DP, Fauci AS: HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993, 362: 355-358. 10.1038/362355a0.

    CAS  PubMed  Google Scholar 

  87. 87.

    Fox CH, Tenner-Racz K, Racz P, Firpo A, Pizzo PA, Fauci AS: Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis. 1991, 164: 1051-1057.

    CAS  PubMed  Google Scholar 

  88. 88.

    Sunila I, Vaccarezza M, Pantaleo G, Fauci AS, Orenstein JM: gp120 is present on the plasma membrane of apoptotic CD4 cells prepared from lymph nodes of HIV-1-infected individuals: an immunoelectron microscopic study. Aids. 1997, 11: 27-32. 10.1097/00002030-199701000-00005.

    CAS  PubMed  Google Scholar 

  89. 89.

    Vlahakis SR, Algeciras-Schimnich A, Bou G, Heppelmann CJ, Villasis-Keever A, Collman RC, Paya CV: Chemokine-receptor activation by env determines the mechanism of death in HIV-infected and uninfected T lymphocytes. J Clin Invest. 2001, 107: 207-215.

    PubMed Central  CAS  PubMed  Google Scholar 

  90. 90.

    Loetscher P, Gong JH, Dewald B, Baggiolini M, Clark-Lewis I: N-terminal peptides of stromal cell-derived factor-1 with CXC chemokine receptor 4 agonist and antagonist activities. J Biol Chem. 1998, 273: 22279-22283. 10.1074/jbc.273.35.22279.

    CAS  PubMed  Google Scholar 

  91. 91.

    Nagasawa T, Nakajima T, Tachibana K, Iizasa H, Bleul CC, Yoshie O, Matsushima K, Yoshida N, Springer TA, Kishimoto T: Molecular cloning and characterization of a murine pre-B-cell growth-stimulating factor/stromal cell-derived factor 1 receptor, a murine homolog of the human immunodeficiency virus 1 entry coreceptor fusin. Proc Natl Acad Sci U S A. 1996, 93: 14726-14729. 10.1073/pnas.93.25.14726.

    PubMed Central  CAS  PubMed  Google Scholar 

  92. 92.

    Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, Springer TA: Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A. 1998, 95: 9448-9453. 10.1073/pnas.95.16.9448.

    PubMed Central  CAS  PubMed  Google Scholar 

  93. 93.

    Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR: Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development [see comments]. Nature. 1998, 393: 595-599. 10.1038/31269.

    CAS  PubMed  Google Scholar 

  94. 94.

    Guillerm C, Coudronnière N, Robert-Hebmann V, Devaux C: Delayed human immunodeficiency virus type 1-induced apoptosis in cells expressing truncated forms of CD4. J Virol. 1998, 72: 1754-1761.

    PubMed Central  CAS  PubMed  Google Scholar 

  95. 95.

    Jacotot E, Krust B, Callebaut C, Laurent-Crawford AG, Blanco J, Hovanessian AG: HIV-1 envelope glycoproteins-mediated apoptosis is regulated by CD4 dependent and independent mechanisms. Apoptosis. 1997, 2: 47-60. 10.1023/A:1026435625144.

    CAS  PubMed  Google Scholar 

  96. 96.

    Biard-Piechaczyk M, Robert-Hebmann V, Richard V, Roland J, Hipskind R, Devaux C: Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated Human Immunodeficiency Virus type 1 envelope glycoprotein (gp120). Virology. 2000, 268: 329-344. 10.1006/viro.1999.0151.

    CAS  PubMed  Google Scholar 

  97. 97.

    Blanco J, Barretina J, Henson G, Bridger G, De Clercq E, Clotet B, Este JA: The CXCR4 antagonist AMD3100 efficiently inhibits cell-surface-expressed human immunodeficiency virus type 1 envelope-induced apoptosis. Antimicrob Agents Chemother. 2000, 44: 51-56.

    PubMed Central  CAS  PubMed  Google Scholar 

  98. 98.

    Biard-Piechaczyk M, Robert-Hebmann V, Roland J, Coudronnière N, Devaux C: Role of CXCR4 in HIV-1-induced apoptosis of cells with a CD4+, CXCR4+ phenotype. Immunol Lett. 1999, 70: 1-3. 10.1016/S0165-2478(99)00124-8.

    CAS  PubMed  Google Scholar 

  99. 99.

    Biard-Piechaczyk M, Robert-Hebmann V, Roland J, Devaux C: Role played by the CD4/CXCR4 complex in HIV-1 gp120env-induced signal transduction leading to apoptosis. ECEAR '99. 1999

    Google Scholar 

  100. 100.

    Blanco J, Jacotot E, Cabrera C, Cardona A, Clotet B, DeClercq E, Esté JA: The implication of the chemokine receptor CXCR4 in HIV-1 envelope protein-induced apoptosis is independent of the G protein-mediated signalling. AIDS. 1999, 13: 909-917. 10.1097/00002030-199905280-00006.

    CAS  PubMed  Google Scholar 

  101. 101.

    Herbein G, VanLint C, Lovett JL, Verdin E: Distinct mechanisms trigger apoptosis in human immunodeficiency virus type 1-infected and in uninfected bystander T lymphocytes. J Virol. 1998, 72: 660-670.

    PubMed Central  CAS  PubMed  Google Scholar 

  102. 102.

    Hesselgesser J, Taub D, Baskar P, Greenberg M, Hoxie J, Kolson DL, Horuk R: Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1α is mediated by the chemokine receptor CXCR4. Current Biology. 1998, 8: 595-598.

    CAS  PubMed  Google Scholar 

  103. 103.

    Roggero R, Robert-Hebmann V, Harrington S, Roland J, Vergne L, Jaleco S, Devaux C, Biard-Piechaczyk M: Binding of human immunodeficiency virus type 1 gp120 to CXCR4 induces mitochondrial transmembrane depolarization and cytochrome c-mediated apoptosis independently of Fas signaling. J Virol. 2001, 75: 7637-7650. 10.1128/JVI.75.16.7637-7650.2001.

    PubMed Central  CAS  PubMed  Google Scholar 

  104. 104.

    Moutouh L, Richmann DD, Corbeil J: HIV-induced apoptosis requires the CD4 cytoplasmic tail and is not Fas-dependent in A2.01 cell line expressing wild type and mutants of the CD4 recpetor. In Retroviruses. 1997, Cold Spring Harbor, N.Y., 283-

    Google Scholar 

  105. 105.

    Cicala C, Arthos J, Rubbert A, Selig S, Wildt K, Cohen O, Fauci A: HIV-1 envelope induces activation of caspase-3 and cleavage of focal adhesion kinase in primary human CD4+ T cells. Proc Natl Acad Sci USA. 2000, 97: 1178-1183. 10.1073/pnas.97.3.1178.

    PubMed Central  CAS  PubMed  Google Scholar 

  106. 106.

    Huang MB, Bond VC: Involvement of protein kinase C in HIV-1 gp120-induced apoptosis in primary endothelium. J Acquir Immune Defic Syndr. 2000, 25: 375-389. 10.1097/00042560-200012150-00001.

    CAS  PubMed  Google Scholar 

  107. 107.

    Ullrich CK, Groopman JE, Ganju RK: HIV-1 gp120- and gp160-induced apoptosis in cultured endothelial cells is mediated by caspases [In Process Citation]. Blood. 2000, 96: 1438-1442.

    CAS  PubMed  Google Scholar 

  108. 108.

    Jekle A, Keppler OT, De Clercq E, Schols D, Weinstein M, Goldsmith MA: In vivo evolution of human immunodeficiency virus type 1 toward increased pathogenicity through CXCR4-mediated killing of uninfected CD4 T cells. J Virol. 2003, 77: 5846-5854. 10.1128/JVI.77.10.5846-5854.2003.

    PubMed Central  CAS  PubMed  Google Scholar 

  109. 109.

    Grivel JC, Margolis LB: CCR5- and CXCR4-tropic HIV-1 are equally cytopathic for their T-cell targets in human lymphoid tissue. Nat Med. 1999, 5: 344-346. 10.1038/6565.

    CAS  PubMed  Google Scholar 

  110. 110.

    Bleul C, Wu LH, Springer TA, MacKay CR: The HIV coreceptors CXCR4 and CCR5 are differencially expressed and regulated on human T lymphocytes. Proc Natl Acad Sci USA. 1997, 94: 1925-1930. 10.1073/pnas.94.5.1925.

    PubMed Central  CAS  PubMed  Google Scholar 

  111. 111.

    Algeciras-Schimnich A, Vlahakis SR, Villasis-Keever A, Gomez T, Heppelmann CJ, Bou G, Paya CV: CCR5 mediates Fas- and caspase-8 dependent apoptosis of both uninfected and HIV infected primary human CD4 T cells. Aids. 2002, 16: 1467-1478. 10.1097/00002030-200207260-00003.

    CAS  PubMed  Google Scholar 

  112. 112.

    Huang MB, Hunter M, Bond VC: Effect of extracellular human immunodeficiency virus type 1 glycoprotein 120 on primary human vascular endothelial cell cultures. AIDS Res Hum Retroviruses. 1999, 15: 1265-1277. 10.1089/088922299310160.

    CAS  PubMed  Google Scholar 

  113. 113.

    Yao Q, Compans RW, Chen C: HIV envelope proteins differentially utilize CXCR4 and CCR5 coreceptors for induction of apoptosis. Virology. 2001, 285: 128-137. 10.1006/viro.2001.0927.

    CAS  PubMed  Google Scholar 

  114. 114.

    Sodroski J, Goh WC, Rosen C, Campbell K, Haseltine WA: Role of the HTLV-III/LAV envelope in syncytium formation and cytopathicity. Nature. 1986, 322: 470-474.

    CAS  PubMed  Google Scholar 

  115. 115.

    Yoffe B, Lewis DE, Petrie BL, Noonan CA, Melnick JL, Hollinger FB: Fusion as a mediator of cytolysis in mixtures of uninfected CD4+ lymphocytes and cells infected by human immunodeficiency virus. Proc Natl Acad Sci USA. 1987, 84: 1429-1433.

    PubMed Central  CAS  PubMed  Google Scholar 

  116. 116.

    Lifson JD, Feinberg MB, Reyes GR, Rabin L, Banapour B, Chakrabarti S, Moss B, Wong-Staal F, Steimer KS, Engleman EG: Induction of CD4-dependent cell fusion by the HTLV-III/LAV envelope glycoprotein. Nature. 1986, 323: 725-728.

    CAS  PubMed  Google Scholar 

  117. 117.

    Stocker H, Scheller C, Jassoy C: Destruction of primary CD4(+) T cells by cell-cell interaction in human immunodeficiency virus type 1 infection in vitro. J Gen Virol. 2000, 81: 1907-1911.

    CAS  PubMed  Google Scholar 

  118. 118.

    Wild CT, Shugars DC, Greenwell TK, McDanal CB, Matthews TJ: Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. Proc Natl Acad Sci U S A. 1994, 91: 9770-9774.

    PubMed Central  CAS  PubMed  Google Scholar 

  119. 119.

    Blanco J, Barretina J, Ferri KF, Jacotot E, Gutierrez A, Armand-Ugon M, Cabrera C, Kroemer G, Clotet B, Este JA: Cell-surface-expressed HIV-1 envelope induces the death of CD4 T cells during GP41-mediated hemifusion-like events. Virology. 2003, 305: 318-329. 10.1006/viro.2002.1764.

    CAS  PubMed  Google Scholar 

  120. 120.

    Navia BA, Cho ES, Petito CK, Price RW: The AIDS dementia complex: II. Neuropathology. Ann Neurol. 1986, 19: 525-535.

    CAS  PubMed  Google Scholar 

  121. 121.

    Frankel SS, Wenig BM, Burke AP, Mannan P, Thompson LD, Abbondanzo SL, Nelson AM, Pope M, Steinman RM: Replication of HIV-1 in dendritic cell-derived syncytia at the mucosal surface of the adenoid. Science. 1996, 272: 115-117.

    CAS  PubMed  Google Scholar 

  122. 122.

    Scheller C, Jassoy C: Syncytium formation amplifies apoptotic signals: a new view on apoptosis in HIV infection in vitro. Virology. 2001, 282: 48-55. 10.1006/viro.2000.0811.

    CAS  PubMed  Google Scholar 

  123. 123.

    Roumier T, Castedo M, Perfettini JL, Andreau K, Metivier D, Zamzami N, Kroemer G: Mitochondrion-dependent caspase activation by the HIV-1 envelope. Biochem Pharmacol. 2003, 66: 1321-1329. 10.1016/S0006-2952(03)00480-5.

    CAS  PubMed  Google Scholar 

  124. 124.

    Castedo M, Roumier T, Blanco J, Ferri KF, Barretina J, Tintignac LA, Andreau K, Perfettini JL, Amendola A, Nardacci R, Leduc P, Ingber DE, Druillennec S, Roques B, Leibovitch SA, Vilella-Bach M, Chen J, Este JA, Modjtahedi N, Piacentini , Kroemer G: Sequential involvement of Cdk1, mTOR and p53 in apoptosis induced by the HIV-1 envelope. Embo J. 2002, 21: 4070-4080. 10.1093/emboj/cdf391.

    PubMed Central  CAS  PubMed  Google Scholar 

  125. 125.

    Ferri KF, Jacotot E, Blanco J, Este JA, Zamzami N, Susin SA, Xie Z, Brothers G, Reed JC, Penninger JM, Kroemer G: Apoptosis Control in Syncytia Induced by the HIV Type 1-Envelope Glycoprotein Complex. Role of mitochondria and caspases. J Exp Med. 2000, 192: 1081-1092. 10.1084/jem.192.8.1081.

    PubMed Central  CAS  PubMed  Google Scholar 

  126. 126.

    Roederer M, Dubs JG, Anderson MT, Raju PA, Herzenberg LA: CD8 naive T cell counts decrease progressively in HIV-infected adults. J Clin Invest. 1995, 95: 2061-2066.

    PubMed Central  CAS  PubMed  Google Scholar 

  127. 127.

    Pantaleo G, Graziosi C, Demarest JF, Cohen OJ, Vaccarezza M, Gantt K, Muro-Cacho C, Fauci AS: Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection. Immunol Rev. 1994, 140: 105-130.

    CAS  PubMed  Google Scholar 

  128. 128.

    Mueller YM, De Rosa SC, Hutton JA, Witek J, Roederer M, Altman JD, Katsikis PD: Increased CD95/Fas-induced apoptosis of HIV-specific CD8(+) T cells. Immunity. 2001, 15: 871-882. 10.1016/S1074-7613(01)00246-1.

    CAS  PubMed  Google Scholar 

  129. 129.

    Petrovas C, Mueller YM, Dimitriou ID, Bojczuk PM, Mounzer KC, Witek J, Altman JD, Katsikis PD: HIV-specific CD8(+) T cells exhibit markedly reduced levels of Bcl-2 and Bcl-x(L). J Immunol. 2004, 172: 4444-4453.

    CAS  PubMed  Google Scholar 

  130. 130.

    Herbein G, Mahlknecht U, Batliwalla F, Gregersen P, Pappas T, Butler J, O'Brien WA, Verdin E: Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4. Nature. 1998, 395: 189-194. 10.1038/26026.

    CAS  PubMed  Google Scholar 

  131. 131.

    Esser MT, Bess JW, Suryanarayana K, Chertova E, Marti D, Carrington M, Arthur LO, Lifson JD: Partial activation and induction of apoptosis in CD4(+) and CD8(+) T lymphocytes by conformationally authentic noninfectious human immunodeficiency virus type 1. J Virol. 2001, 75: 1152-1164. 10.1128/JVI.75.3.1152-1164.2001.

    PubMed Central  CAS  PubMed  Google Scholar 

  132. 132.

    Grelli S, d'Ettorre G, Lauria F, Montella F, Di Traglia L, Lichtner M, Vullo V, Favalli C, Vella S, Macchi B, Mastino A: Inverse correlation between CD8+ lymphocyte apoptosis and CD4+ cell counts during potent antiretroviral therapy in HIV patients. J Antimicrob Chemother. 2004, 53: 494-500. 10.1093/jac/dkh105.

    CAS  PubMed  Google Scholar 

  133. 133.

    Mastroianni CM, d'Ettorre G, Forcina G, Vullo V: Teaching tired T cells to fight HIV: time to test IL-15 for immunotherapy?. Trends Immunol. 2004, 25: 121-125. 10.1016/

    CAS  PubMed  Google Scholar 

  134. 134.

    Mueller YM, Bojczuk PM, Halstead ES, Kim AH, Witek J, Altman JD, Katsikis PD: IL-15 enhances survival and function of HIV-specific CD8+ T cells. Blood. 2003, 101: 1024-1029. 10.1182/blood-2002-07-1957.

    CAS  PubMed  Google Scholar 

  135. 135.

    Ahmad R, Sindhu ST, Toma E, Morisset R, Ahmad A: Studies on the production of IL-15 in HIV-infected/AIDS patients. J Clin Immunol. 2003, 23: 81-90. 10.1023/A:1022568626500.

    CAS  PubMed  Google Scholar 

  136. 136.

    Buzy J, Brenneman DE, Pert CB, Martin A, Salazar A, Ruff MR: Potent gp120-like neurotoxic activity in the cerebrospinal fluid of HIV-infected individuals is blocked by peptide T. Brain Res. 1992, 598: 10-18. 10.1016/0006-8993(92)90161-2.

    CAS  PubMed  Google Scholar 

  137. 137.

    Jones MV, Bell JE, Nath A: Immunolocalization of HIV envelope gp120 in HIV encephalitis with dementia. Aids. 2000, 14: 2709-2713. 10.1097/00002030-200012010-00010.

    CAS  PubMed  Google Scholar 

  138. 138.

    Banks WA, Kastin AJ, Akerstrom V: HIV-1 protein gp120 crosses the blood-brain barrier: role of adsorptive endocytosis. Life Sci. 1997, 61: PL119-125. 10.1016/S0024-3205(97)00597-3.

    CAS  PubMed  Google Scholar 

  139. 139.

    Lavi E, Kolson DL, Ulrich AM, Fu L, Gonzalez-Scarano F: Chemokine receptors in the human brain and their relationship to HIV infection. J Neurovirol. 1998, 4: 301-311.

    CAS  PubMed  Google Scholar 

  140. 140.

    Kaul M, Garden GA, Lipton SA: Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature. 2001, 410: 988-994. 10.1038/35073667.

    CAS  PubMed  Google Scholar 

  141. 141.

    McGeer PL, McGeer EG: The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev. 1995, 21: 195-218. 10.1016/0165-0173(95)00011-9.

    CAS  PubMed  Google Scholar 

  142. 142.

    Glass JD, Fedor H, Wesselingh SL, McArthur JC: Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol. 1995, 38: 755-762.

    CAS  PubMed  Google Scholar 

  143. 143.

    Shi B, De Girolami U, He J, Wang S, Lorenzo A, Busciglio J, Gabuzda D: Apoptosis induced by HIV-1 infection of the central nervous system. J Clin Invest. 1996, 98: 1979-1990.

    PubMed Central  CAS  PubMed  Google Scholar 

  144. 144.

    Gendelman HE, Persidsky Y, Ghorpade A, Limoges J, Stins M, Fiala M, Morrisett R: The neuropathogenesis of the AIDS dementia complex. Aids. 1997, 11 (Suppl A): S35-45.

    PubMed  Google Scholar 

  145. 145.

    Brenneman DE, Westbrook GL, Fitzgerald SP, Ennist DL, Elkins KL, Ruff MR, Pert CB: Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature. 1988, 335: 639-642. 10.1038/335639a0.

    CAS  PubMed  Google Scholar 

  146. 146.

    Dreyer EB, Kaiser PK, Offermann JT, Lipton SA: HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science. 1990, 248: 364-367.

    CAS  PubMed  Google Scholar 

  147. 147.

    Bagetta G, Corasaniti MT, Berliocchi L, Navarra M, Finazzi-Agro A, Nistico G: HIV-1 gp120 produces DNA fragmentation in the cerebral cortex of rat. Biochem Biophys Res Commun. 1995, 211: 130-136. 10.1006/bbrc.1995.1787.

    CAS  PubMed  Google Scholar 

  148. 148.

    Kaul M, Lipton S: Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proc Natl Acad Sci. 1999, 96: 8212-8216. 10.1073/pnas.96.14.8212.

    PubMed Central  CAS  PubMed  Google Scholar 

  149. 149.

    Zheng J, Thylin M, Ghorpade A, Xiong H, Persidsky Y, Cotter R, Niemann D, Che M, Zeng Y, Gelbard H, Shepard R, Swartz J, Gendelman H: Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia. J Neuroimmunol. 1999, 3: 185-200. 10.1016/S0165-5728(99)00049-1.

    Google Scholar 

  150. 150.

    Zhang K, Rana F, Silva C, Ethier J, Wehrly K, Chesebro B, Power C: Human immunodeficiency virus type 1 envelope-mediated neuronal death: uncoupling of viral replication and neurotoxicity. J Virol. 2003, 77: 6899-6912. 10.1128/JVI.77.12.6899-6912.2003.

    PubMed Central  CAS  PubMed  Google Scholar 

  151. 151.

    Mollace V, Salvemini D, Riley DP, Muscoli C, Iannone M, Granato T, Masuelli L, Modesti A, Rotiroti D, Nistico R, Bertoli A, Perno CF, Aquaro S: The contribution of oxidative stress in apoptosis of human-cultured astroglial cells induced by supernatants of HIV-1-infected macrophages. J Leukoc Biol. 2002, 71: 65-72.

    CAS  PubMed  Google Scholar 

  152. 152.

    Sabri F, Titanji K, De Milito A, Chiodi F: Astrocyte activation and apoptosis: their roles in the neuropathology of HIV infection. Brain Pathol. 2003, 13: 84-94.

    PubMed  Google Scholar 

  153. 153.

    Thompson KA, McArthur JC, Wesselingh SL: Correlation between neurological progression and astrocyte apoptosis in HIV-associated dementia. Ann Neurol. 2001, 49: 745-752. 10.1002/ana.1011.

    CAS  PubMed  Google Scholar 

  154. 154.

    Corasaniti MT, Rotiroti D, Nappi G, Bagetta G: Neurobiological mediators of neuronal apoptosis in experimental neuroAIDS. Toxicol Lett. 2003, 139: 199-206. 10.1016/S0378-4274(02)00434-4.

    CAS  PubMed  Google Scholar 

  155. 155.

    Garden GA, Budd SL, Tsai E, Hanson L, Kaul M, D'Emilia DM, Friedlander RM, Yuan J, Masliah E, Lipton SA: Caspase cascades in human immunodeficiency virus-associated neurodegeneration. J Neurosci. 2002, 22: 4015-4024.

    CAS  PubMed  Google Scholar 

  156. 156.

    Wesselingh SL, Thompson KA: Immunopathogenesis of HIV-associated dementia. Curr Opin Neurol. 2001, 14: 375-379. 10.1097/00019052-200106000-00018.

    CAS  PubMed  Google Scholar 

  157. 157.

    Ohagen A, Ghosh S, He J, Huang K, Chen Y, Yuan M, Osathanondh R, Gartner S, Shi B, Shaw G, Gabuzda D: Apoptosis induced by infection of primary brain cultures with diverse human immunodeficiency virus type 1 isolates: evidence for a role of the envelope. J virol. 1999, 73: 897-906.

    PubMed Central  CAS  PubMed  Google Scholar 

  158. 158.

    Power C, McArthur JC, Johnson RT, Griffin DE, Glass JD, Perryman S, Chesebro B: Demented and nondemented patients with AIDS differ in brain-derived human immunodeficiency virus type 1 envelope sequences. J Virol. 1994, 68: 4643-4649.

    PubMed Central  CAS  PubMed  Google Scholar 

  159. 159.

    Alvarez Losada S, Canto-Nogues C, Munoz-Fernandez MA: A new possible mechanism of human immunodeficiency virus type 1 infection of neural cells. Neurobiol Dis. 2002, 11: 469-478. 10.1006/nbdi.2002.0566.

    CAS  PubMed  Google Scholar 

  160. 160.

    Hesselgesser J, Halks-Miller M, DelVecchio V, Peiper SC, Hoxie J, Kolson DL, Taub D, Horuk R: CD4-independent association between HIV-1 gp120 and CXCR4: functional chemokine receptors are expressed in human neurons. Curr Biol. 1997, 7: 112-121. 10.1016/S0960-9822(06)00055-8.

    CAS  PubMed  Google Scholar 

  161. 161.

    Catani MV, Corasaniti MT, Navarra M, Nistico G, Finazzi-Agro A, Melino G: gp120 induces cell death in human neuroblastoma cells through the CXCR4 and CCR5 chemokine receptors. J Neurochem. 2000, 74: 2373-2379. 10.1046/j.1471-4159.2000.0742373.x.

    CAS  PubMed  Google Scholar 

  162. 162.

    Barbaro G, Fisher SD, Lipshultz SE: Pathogenesis of HIV-associated cardiovascular complications. Lancet Infect Dis. 2001, 1: 115-124. 10.1016/S1473-3099(01)00067-6.

    CAS  PubMed  Google Scholar 

  163. 163.

    Twu C, Liu NQ, Popik W, Bukrinsky M, Sayre J, Roberts J, Rania S, Bramhandam V, Roos KP, MacLellan WR, Fiala M: Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways. Proc Natl Acad Sci U S A. 2002, 99: 14386-14391. 10.1073/pnas.212327899.

    PubMed Central  CAS  PubMed  Google Scholar 

  164. 164.

    Herman ES, Klotman PE: HIV-associated nephropathy: Epidemiology, pathogenesis, and treatment. Semin Nephrol. 2003, 23: 200-208. 10.1053/snep.2003.50018.

    PubMed  Google Scholar 

  165. 165.

    Ray PE, Liu XH, Robinson LR, Reid W, Xu L, Owens JW, Jones OD, Denaro F, Davis HG, Bryant JL: A novel HIV-1 transgenic rat model of childhood HIV-1-associated nephropathy. Kidney Int. 2003, 63: 2242-2253. 10.1046/j.1523-1755.2003.00028.x.

    PubMed  Google Scholar 

  166. 166.

    Kapasi AA, Patel G, Franki N, Singhal PC: HIV-1 gp120-induced tubular epithelial cell apoptosis is mediated through p38-MAPK phosphorylation. Mol Med. 2002, 8: 676-685.

    PubMed Central  CAS  PubMed  Google Scholar 

  167. 167.

    Bica I, McGovern B, Dhar R, Stone D, McGowan K, Scheib R, Snydman DR: Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis. 2001, 32: 492-497. 10.1086/318501.

    CAS  PubMed  Google Scholar 

  168. 168.

    Vlahakis SR, Villasis-Keever A, Gomez TS, Bren GD, Paya CV: Human immunodeficiency virus-induced apoptosis of human hepatocytes via CXCR4. J Infect Dis. 2003, 188: 1455-1460. 10.1086/379738.

    CAS  PubMed  Google Scholar 

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We thank S. Thebault for helpful scientific discussions and careful critical reading of the manuscript. This work was supported by institutional funds from the Centre National de la Recherche Scientifique and the Université Montpellier I and grants from Ensemble contre le SIDA, and by an ANRS fellowship (B. Ahr).

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Ahr, B., Robert-Hebmann, V., Devaux, C. et al. Apoptosis of uninfected cells induced by HIV envelope glycoproteins. Retrovirology 1, 12 (2004).

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  • Human Immunodeficiency Virus
  • Human Immunodeficiency Virus Infection
  • Simian Immunodeficiency Virus
  • Human Immunodeficiency Virus Patient
  • Human Immunodeficiency Virus Disease