Skip to main content

The co-receptor signaling model of HIV-1 pathogenesis in peripheral CD4 T cells


HIV-mediated CD4 depletion is the hallmark of AIDS and is the most reliable predictor of disease progression. While HIV replication is associated with CD4 depletion in general, plasma viremia by itself predicts the rate of CD4 loss only minimally in untreated patients. To resolve this paradox, I hypothesize the existence of a subpopulation of R5X4-signaling viruses. I also suggest that the gradual evolution and emergence of this subpopulation are largely responsible for the slow depletion of peripheral CD4 T cells.


The human immunodeficiency virus (HIV) infects CD4 T cells and causes CD4 depletion which leads to the development of AIDS. In the spectrum of clinical signs associated with HIV infection, CD4 depletion is a hallmark and is one of the most powerful predictors of disease progression. On the other hand, the level of viral replication, as reflected by plasma viral RNA load, has also been suggested to directly predict progression to AIDS and death [1]. Nevertheless, the relationship between plasma viremia and CD4 depletion rate has been a subject of debate [2]. While it is certain that a strong correlation between viral load and CD4 depletion exists when plasma viremia is grouped into different categories (e.g. < 500 copies/ml, 501–3000 copies/ml, >30,000 copies/ml etc.) [1, 3], at the individual level, the presenting viral load poorly predicts the rate of CD4 depletion in untreated patients [2, 4]. To resolve this paradox, here I propose a new hypothesis from a co-receptor signaling perspective based on our recent studies [5]. As shown in Figure 1, I hypothesize that HIV-1 gp120-CXCR4 signaling plays a major role in the gradual depletion of peripheral CD4 T cells during chronic HIV infection.

Figure 1

The co-receptor signaling model of HIV pathogenesis in peripheral CD4 T cells. In this model, I hypothesize that the emergence of the R5X4-signaling viruses (Red dotted lines) is responsible for the slow depletion of peripheral CD4 T cells.

In this model, I separate the disease course into three phases: (1) primary HIV replication, (2) priming, and (3) delayed HIV replication. The primary phase largely involves the efficient replication of CCR5-utilizing, M-tropic viruses such as those replicating in the GI tract [6]. In the second phase, with immune suppression or the consumption of most of the available CCR5 target T cells, viral replication is reduced to a low level. This low-level ongoing viral replication serves as a reservoir that supplies viral mutants to prime the immune system for new target cells. Early on in the priming phase, limited mutations such as one or two amino acid changes in the V3 loop of the viral envelope may give rise to the first CXCR4-priming virus. These small numbers of early viruses may still use CCR5 for entry and replication but can engage CXCR4. This CXCR4 binding may not permit viral entry since successful fusion and entry often require more than two mutations or even mutations outside of the V3 loop [7]. Other virological obstacles may also play a role in preventing the quick emergence of viruses with the X4 phenotype [8]. Nevertheless, these early CXCR4-priming viruses (R5X4-signaling viruses) can trigger signal transduction in CXCR4 cells without actually infecting and replicating in these cells. On the other hand, aberrant CXCR4 signaling may mediate CD4 T cell dysfunction and contribute to chronic immune activation, gradually shifting these otherwise restrictive cells towards the direction of permissiveness. With continued engagement of the CXCR4 receptor, the priming event may eventually lead to the emergence of the X4 viral phenotype and its viral replication in some patients. The newly emerged CXCR4-utilizing, T-tropic viruses would then find a large pool of targets and initiate a new phase of viral replication, the third delayed replication phase, which could result in rapid CD4 depletion and fast progression to AIDS [9]. In some patients, the full X4 phenotype may never arise, but the X4 priming could remain an ongoing process that would provoke slow CD4 depletion and disease progression.

The central tenets of this new signaling model are the hypothetical existence of the R5X4-signaling viruses during chronic infection and the direct association of these viruses with CD4 depletion. The R5X4-signaling viruses are predicted to be a minority during the chronic phase with no strong replication or selection advantage over other R5 viruses [10], largely because of the continuous use of CCR5-positive cells for replication. Moreover, the signaling and depletion of CD4 T cells by the R5X4-signaling mutants are likely to be loosely correlated with the overall predominance of R5 viruses which are less pathogenic to peripheral CD4 T cells in general. Nevertheless, the emergence of the R5X4-signaling viruses does depend on the pool of R5 viruses; thus, while HIV-1 replication is overall associated with CD4 depletion [1], the use of total plasma viral RNA load, a measurement of mostly R5 viruses, is a poor predictor of the slow CD4 loss in patients [2]. The very existence of the hypothetical R5X4-signaling subpopulation that can directly cause CD4 loss would be a reasonable explanation for the observed paradoxical relationship between total viral load and CD4 depletion [1, 2].


The different T cell targets of M-tropic and T-tropic viruses

The natural course of HIV infection almost always starts with the robust replication of the CCR5-ultilizing M-tropic viruses [6, 11, 12]. The R5 viruses can quickly infect, replicate and kill a large number of target cells such as the active memory CD4 T cells present in the GI tract [6, 11, 12]. This early process occurs in both HIV-1 infection of humans [6, 12] and in the pathogenic and non-pathogenic SIV infection of monkeys [11], and can result in lasting pathogenic insults [13] to or non-pathogenic effects [14, 15] on the immune system. With the onset of the asymptomatic phase following the acute infection, viral diversification occurs. In about 50% of infected patients (mostly subtype-B infection), there is a viral switch in the co-receptor usage, from CCR5 to CXCR4, at late stages of disease. This switch correlates with faster CD4 depletion and more rapid disease progression towards AIDS [9, 1619]. The late emergence of the CXCR4-utilizing viruses may be a reflection of the restrictive nature of the X4 viral target cells. In the human immune system, a majority of CD4 T cells in the peripheral blood are CXCR4-positive, resting CD4 T cells. These cells pose numerous restrictions that the virus has to overcome to replicate. Firstly, the viral envelope has to be mutated to engage the CXCR4 receptor [20], and the mutations have to accumulate to a sufficient degree to permit successful viral entry [7, 8]. Secondly, the virus has to modulate the immune system, either by inducing cytokines [2123] or facilitating transient immune activation to permit viral integration [2429]. Even with successful integration, the virus has to induce or rely on chronic immune activation to maintain stable gene expression and viral production [22, 23, 30]. Recently, we demonstrated that the static cytoskeletal actin in resting CD4 T cells is also a barrier for viral intracellular migration [5]. To overcome this restriction, the virus has to rely on signal transduction via the viral envelope binding to CXCR4, which triggers the activation of an actin depolymerization factor cofilin in resting T cells. This cofilin activation increases cortical actin treadmilling and actin dynamics, permitting viral migration across the cortical actin barrier [5].

Given the critical role that CXCR4 signaling plays in HIV infection of peripheral CD4 T cells, it is possible that HIV-mediated aberrant signalling through CXCR4 may contribute to viral pathogenesis in these cells. It has long been recognized that the residual CD4 cells in HIV-infected subjects have multiple functional abnormalities such as anergy [31, 32], loss of T helper function [33], and abnormal T cell homing and migration [34, 35], all of which result from the bystander effect [36]. These T cell abnormalities suggest that although they are not directly infected, these residual CD4 T cells may have been engaged by viruses or viral factors, and their signaling responses to environmental stimuli have been profoundly altered.

Supporting evidence from bioinformatics studies of the evolution of the HIV envelope protein

In contrast to the R5 viruses, the capacity of the late-emerging X4 viruses to cause rapid CD4 depletion clearly demonstrates the pathogenic importance of the CXCR4-engaging viruses [9, 1619]. Interestingly, by using bioinformatics approaches such as neural networks [37], PSSM [38, 39] or 11/25 genotype [3943], the potential of the R5 virus to switch to the more pathogenic X4 virus can be predicted based on the charged residues within the V3 loop, particularly at the 11 and 25 positions of V3. Remarkably, even though approximately 50% of patients do not actually acquire the X4 phenotype ever in their disease, the V3 genotypes were found to be associated with more rapid CD4 depletion and faster disease progression [44]. The predictive value of the X4 genotypes for CD4 depletion presumably hinges upon the occurrence of the X4 phenotype. Yet, it is very possible that these X4 genotypes may reflect the actual capacity of the viral envelopes to engage and signal through CXCR4. Therefore, the direct correlation of CD4 depletion with the X4 genotypes in the absence of the X4 phenotype is a strong indication of the possible existence of the R5X4-signaling viruses. As a matter of fact, a recent study using massive pyrosequencing of the V3 loop has found that clusters of the R5 proviral genomes harboured in patients' monocytes carry mutations with the X4 genotypes [45]. Similar R5 genotypic evolution was also observed even in patients maintaining exclusively the R5 viruses [46]. In the absence of the R5-to-X4 phenotypic switch, the R5 phenotype does evolve with disease progression in properties such as a decreasing sensitivity to the neutralization by CC chemokines [47] and an increasing capacity for direct and DC-SIGN-mediated trans-infection of T cells [46]. In addition, it has also been shown that in the peripheral blood mononuclear cells of infected patients, different sub-populations of infected cells co-exist, and some of these cells, such as infected monocytes and memory T cells, have a slow decay rate [48]. These cells may serve as the seeds for the development of the R5X4-signaling phenotype.

The balance between gp120 priming T cells and triggering apoptosis

In addition to transducing signals to promote HIV infection [5, 4951], HIV envelope binding to the chemokine co-receptors has also been suggested to trigger apoptosis of CD4 T cells [5256]. Even before the identification of the chemokine co-receptors, gp120 was proposed to trigger activation-dependent T cell apoptosis through the CD4 receptor [5759]. This suggestion was based on a similar mechanism observed in the activation of murine lymphocytes in which pre-stimulation of the CD4 receptor triggered apoptosis when the cells were also activated through the T cell receptor [60]. It appears that engagement of the CD4 receptor alone, either by the R5 or X4 viruses, may not be sufficient to trigger apoptosis; CD4 signaling promotes apoptosis largely in the presence of signals that also activate CD4 T cells [5759]. The R5-viruses may induce apoptosis through CCR5 in active memory CD4 T cells [61]. The majority of peripheral resting CD4 T cells, however, have either no CCR5 or low levels of CCR5 receptor. It is possible that the apoptotic process in resting CD4 T cells is triggered by the X4 viruses or X4-signaling viruses by binding and signaling through CXCR4.

HIV envelope-mediated apoptosis has been implicated to contribute to the depletion of either infected or uninfected CD4 T cells [57]. Nevertheless, from a purely virological point of view, triggering apoptosis, especially at the earliest time of infection, is a misfortune and is something that a virus should always avoid. For example, even the fast replicating, extremely cytolytic viruses such as baculovirus encode anti-apoptotic proteins to avoid triggering apoptosis at an early time [62]. In HIV infection, latently infected resting CD4 T cells, with a half life as long as 3 to 4 years [63], were frequently detected to persist in patients [6466]. In addition, it has also been shown that in contrast to triggering apoptosis, the HIV-1 envelope can induce productive viral replication from the resting CD4 T cells of HIV-infected patients [51]. Therefore, it is possible that even though the HIV envelope triggers apoptosis of CD4 T cells, this may not frequently occur until the X4 signaling viral population reaches a significant level. In other words, the balance between CXCR4 priming and CXCR4 triggering apoptosis is probably regulated by signal strength; apoptosis would require higher viral dosages. In the HIV disease course, initially, low levels of X4 signaling viruses may prime CD4 T cells for infection, whereas at a late stage when levels of X4 signaling viruses are high especially with the emergence of the X4 phenotype, triggering apoptosis may be more common and may directly contribute to CD4 depletion.

It has also been suggested that HIV-infected cells downregulate PD-1, whereas uninfected bystander cells do not [67]. PD-1 downregulation prevents cells from early apoptosis. Presumably, this mechanism would enrich HIV+ CD4 T cells, facilitating the amplification of X4 viruses. Nevertheless, this mechanism probably would not be in play until the late emergence of the X4 phenotype.

Basic characteristics associated with the hypothetic R5X4-signalingviruses

In the chemokine co-receptor signaling model, the hypothetic R5X4-signaling viruses are proposed to be responsible for the slow depletion of peripheral CD4 T cells. Experimental demonstration of such R5X4-signaling viruses requires the establishment of certain basic criteria. Firstly, the R5X4-signaling viruses are phenotypically R5 viruses. They should enter CD4+CCR5+ but not CD4+CXCR4+ indicator cells in co-receptor tropism assays. These viruses should also demonstrate susceptibility to antagonists specific for CCR5. Secondly, the envelope protein from the R5X4-signaling viruses should be able to bind to CXCR4 in non-cell-based in vitro binding assays; this interaction can be competitively inhibited by a CXCR4 antagonist. The ability to interact with CXCR4 does not equate with the capability to trigger fusion, which requires the involvement of other regions in addition to the V3 loop of gp120. There are likely varying degrees of affinity for CXC4 among the R5X4-signaling viruses. Thirdly, the R5X4-signalingviruses should demonstrate the ability to trigger signal transduction through CXCR4 in resting CD4 T cells. The signaling may also be shut down by a CXCR4 antagonist. The issue is complex because CXCR4 signaling is known to be diverse and can activate an array of downstream targets such as Pyk2 [68], PI3K, Akt [69, 70], Erk-1/2 [70], and cofilin [5]. It is expected that not every one of these targets is directly involved in HIV infection and pathogenesis. In addition, there are also dosage and affinity-dependent differences in activating specific pathways. For example, at low dosages, SDF-1 binding to CXCR4 attracts CD4 T cells, whereas at high dosages, the same binding does the opposite to repel CD4 cells [35, 71]. Therefore, the critical issue becomes what downstream target should be used as a readout for measuring CXCR4 signaling at a defined viral dosage. Currently, we propose coflin as a final readout for measuring CXCR4 signaling in CD4 T cells because we have demonstrated that it is a direct downstream target of gp120-CXCR4 interaction, and its activation facilitates viral infection. Nevertheless, clinical studies are required to determine whether activation of cofilin or any other CXCR4 downstream target is directly associated with CD4 depletion and HIV disease progression. Establishment of this relationship is an essential step to experimentally identify the R5X4-signalingsubpopulation.


The co-receptor signaling model implies that the HIV envelope plays a major role in the slow depletion of peripheral CD4 T cells. Although HIV directly infects only a very small percentage of peripheral CD4 T cells (0.2–16.4 HIV-latently infected cells per 106 resting CD4 T cells [64]), the ability of the viral envelope to alter T cell function through signal transduction should not be underestimated. This hypothesis highlights the need for a thorough examination of the signaling properties of HIV quasispecies in patients. I also speculate that these R5X4-signaling viruses may cause cofilin activation in resting CD4 T cells as suggested in our recent studies [5, 72]. Conceivably, in comparison with the use of plasma viral load as a readout, cofilin activation would be a more direct reflection of CD4 dysfunction and may serve as an early marker for predicting CD4 depletion.



Macrophage Tropic


T cell Tropic








  1. 1.

    Mellors JW, Rinaldo CR, Gupta P, White RM, Todd JA, Kingsley LA: Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996, 272: 1167-1170. 10.1126/science.272.5265.1167.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Rodriguez B, Sethi AK, Cheruvu VK, Mackay W, Bosch RJ, Kitahata M, Boswell SL, Mathews WC, Bangsberg DR, Martin J, et al: Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. Jama. 2006, 296: 1498-1506. 10.1001/jama.296.12.1498.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Mellors JW, Munoz A, Giorgi JV, Margolick JB, Tassoni CJ, Gupta P, Kingsley LA, Todd JA, Saah AJ, Detels R, et al: Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med. 1997, 126: 946-954.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Henry WK, Tebas P, Lane HC: Explaining, predicting, and treating HIV-associated CD4 cell loss: after 25 years still a puzzle. Jama. 2006, 296: 1523-1525. 10.1001/jama.296.12.1523.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Yoder A, Yu D, Dong L, Iyer SR, Xu X, Kelly J, Liu J, Wang W, Vorster PJ, Agulto L, et al: HIV envelope-CXCR4 signaling activates cofilin to overcome cortical actin restriction in resting CD4 T cells. Cell. 2008, 134: 782-792. 10.1016/j.cell.2008.06.036.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  6. 6.

    Mehandru S, Poles MA, Tenner-Racz K, Horowitz A, Hurley A, Hogan C, Boden D, Racz P, Markowitz M: Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med. 2004, 200: 761-770. 10.1084/jem.20041196.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  7. 7.

    Pastore C, Nedellec R, Ramos A, Pontow S, Ratner L, Mosier DE: Human immunodeficiency virus type 1 coreceptor switching: V1/V2 gain-of-fitness mutations compensate for V3 loss-of-fitness mutations. J Virol. 2006, 80: 750-758. 10.1128/JVI.80.2.750-758.2006.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  8. 8.

    Pastore C, Ramos A, Mosier DE: Intrinsic obstacles to human immunodeficiency virus type 1 coreceptor switching. J Virol. 2004, 78: 7565-7574. 10.1128/JVI.78.14.7565-7574.2004.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  9. 9.

    Fenyo EM, Morfeldt-Manson L, Chiodi F, Lind B, von Gegerfelt A, Albert J, Olausson E, Asjo B: Distinct replicative and cytopathic characteristics of human immunodeficiency virus isolates. J Virol. 1988, 62: 4414-4419.

    PubMed Central  CAS  PubMed  Google Scholar 

  10. 10.

    Bonhoeffer S, Holmes EC, Nowak MA: Causes of HIV diversity. Nature. 1995, 376: 125-10.1038/376125a0.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL, Rosenzweig M, Johnson RP, Desrosiers RC, Lackner AA: Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science. 1998, 280: 427-431. 10.1126/science.280.5362.427.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase AT, Douek DC: CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 2004, 200: 749-759. 10.1084/jem.20040874.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  13. 13.

    Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, et al: Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006, 12: 1365-1371. 10.1038/nm1511.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Gordon SN, Klatt NR, Bosinger SE, Brenchley JM, Milush JM, Engram JC, Dunham RM, Paiardini M, Klucking S, Danesh A, et al: Severe depletion of mucosal CD4+ T cells in AIDS-free simian immunodeficiency virus-infected sooty mangabeys. J Immunol. 2007, 179: 3026-3034.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  15. 15.

    Pandrea IV, Gautam R, Ribeiro RM, Brenchley JM, Butler IF, Pattison M, Rasmussen T, Marx PA, Silvestri G, Lackner AA, et al: Acute loss of intestinal CD4+ T cells is not predictive of simian immunodeficiency virus virulence. J Immunol. 2007, 179: 3035-3046.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  16. 16.

    Schuitemaker H, Koot M, Kootstra NA, Dercksen MW, de Goede RE, van Steenwijk RP, Lange JM, Schattenkerk JK, Miedema F, Tersmette M: Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. J Virol. 1992, 66: 1354-1360.

    PubMed Central  CAS  PubMed  Google Scholar 

  17. 17.

    Tersmette M, Gruters RA, de Wolf F, de Goede RE, Lange JM, Schellekens PT, Goudsmit J, Huisman HG, Miedema F: Evidence for a role of virulent human immunodeficiency virus (HIV) variants in the pathogenesis of acquired immunodeficiency syndrome: studies on sequential HIV isolates. J Virol. 1989, 63: 2118-2125.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. 18.

    Shankarappa R, Margolick JB, Gange SJ, Rodrigo AG, Upchurch D, Farzadegan H, Gupta P, Rinaldo CR, Learn GH, He X, et al: Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection. J Virol. 1999, 73: 10489-10502.

    PubMed Central  CAS  PubMed  Google Scholar 

  19. 19.

    Blaak H, van't Wout AB, Brouwer M, Hooibrink B, Hovenkamp E, Schuitemaker H: In vivo HIV-1 infection of CD45RA(+)CD4(+) T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4(+) T cell decline. Proc Natl Acad Sci USA. 2000, 97: 1269-1274. 10.1073/pnas.97.3.1269.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  20. 20.

    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. 10.1126/science.272.5263.872.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Valdez H, Lederman MM: Cytokines and cytokine therapies in HIV infection. AIDS Clin Rev. 1997, 187-228.

    Google Scholar 

  22. 22.

    Unutmaz D, KewalRamani VN, Marmon S, Littman DR: Cytokine signals are sufficient for HIV-1 infection of resting human T lymphocytes. J Exp Med. 1999, 189: 1735-1746. 10.1084/jem.189.11.1735.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  23. 23.

    Chun TW, Engel D, Mizell SB, Ehler LA, Fauci AS: Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines. J Exp Med. 1998, 188: 83-91. 10.1084/jem.188.1.83.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  24. 24.

    Spina CA, Kwoh TJ, Chowers MY, Guatelli JC, Richman DD: The importance of nef in the induction of human immunodeficiency virus type 1 replication from primary quiescent CD4 lymphocytes. J Exp Med. 1994, 179: 115-123. 10.1084/jem.179.1.115.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Schrager JA, Marsh JW: HIV-1 Nef increases T cell activation in a stimulus-dependent manner. Proc Natl Acad Sci USA. 1999, 96: 8167-8172. 10.1073/pnas.96.14.8167.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  26. 26.

    Ott M, Emiliani S, Van Lint C, Herbein G, Lovett J, Chirmule N, McCloskey T, Pahwa S, Verdin E: Immune hyperactivation of HIV-1-infected T cells mediated by Tat and the CD28 pathway. Science. 1997, 275: 1481-1485. 10.1126/science.275.5305.1481.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Fenard D, Yonemoto W, de Noronha C, Cavrois M, Williams SA, Greene WC: Nef is physically recruited into the immunological synapse and potentiates T cell activation early after TCR engagement. J Immunol. 2005, 175: 6050-6057.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Keppler OT, Tibroni N, Venzke S, Rauch S, Fackler OT: Modulation of specific surface receptors and activation sensitization in primary resting CD4+ T lymphocytes by the Nef protein of HIV-1. J Leukoc Biol. 2006, 79: 616-627. 10.1189/jlb.0805461.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Wu Y, Marsh JW: Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Science. 2001, 293: 1503-1506. 10.1126/science.1061548.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Brooks DG, Arlen PA, Gao L, Kitchen CM, Zack JA: Identification of T cell-signaling pathways that stimulate latent HIV in primary cells. Proc Natl Acad Sci USA. 2003, 100: 12955-12960. 10.1073/pnas.2233345100.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  31. 31.

    Gurley RJ, Ikeuchi K, Byrn RA, Anderson K, Groopman JE: CD4+ lymphocyte function with early human immunodeficiency virus infection. Proc Natl Acad Sci USA. 1989, 86: 1993-1997. 10.1073/pnas.86.6.1993.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  32. 32.

    Masci AM, Galgani M, Cassano S, De Simone S, Gallo A, De Rosa V, Zappacosta S, Racioppi L: HIV-1 gp120 induces anergy in naive T lymphocytes through CD4-independent protein kinase-A-mediated signaling. J Leukoc Biol. 2003, 74: 1117-1124. 10.1189/jlb.0503239.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Clerici M, Stocks NI, Zajac RA, Boswell RN, Lucey DR, Via CS, Shearer GM: Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging. J Clin Invest. 1989, 84: 1892-1899. 10.1172/JCI114376.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  34. 34.

    Chen JJ, Cloyd MW: The potential importance of HIV-induction of lymphocyte homing to lymph nodes. Int Immunol. 1999, 11: 1591-1594. 10.1093/intimm/11.10.1591.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Brainard DM, Tharp WG, Granado E, Miller N, Trocha AK, Ren XH, Conrad B, Terwilliger EF, Wyatt R, Walker BD, Poznansky MC: Migration of antigen-specific T cells away from CXCR4-binding human immunodeficiency virus type 1 gp120. J Virol. 2004, 78: 5184-5193. 10.1128/JVI.78.10.5184-5193.2004.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  36. 36.

    Tough DF, Borrow P, Sprent J: Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science. 1996, 272: 1947-1950. 10.1126/science.272.5270.1947.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Resch W, Hoffman N, Swanstrom R: Improved success of phenotype prediction of the human immunodeficiency virus type 1 from envelope variable loop 3 sequence using neural networks. Virology. 2001, 288: 51-62. 10.1006/viro.2001.1087.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Jensen MA, Li FS, van't Wout AB, Nickle DC, Shriner D, He HX, McLaughlin S, Shankarappa R, Margolick JB, Mullins JI: Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences. J Virol. 2003, 77: 13376-13388. 10.1128/JVI.77.24.13376-13388.2003.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  39. 39.

    Jensen MA, Coetzer M, van't Wout AB, Morris L, Mullins JI: A reliable phenotype predictor for human immunodeficiency virus type 1 subtype C based on envelope V3 sequences. J Virol. 2006, 80: 4698-4704. 10.1128/JVI.80.10.4698-4704.2006.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  40. 40.

    Fouchier RA, Groenink M, Kootstra NA, Tersmette M, Huisman HG, Miedema F, Schuitemaker H: Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule. J Virol. 1992, 66: 3183-3187.

    PubMed Central  CAS  PubMed  Google Scholar 

  41. 41.

    Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, Lifson JD, Bonhoeffer S, Nowak MA, Hahn BH, et al: Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995, 373: 117-122. 10.1038/373117a0.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Jensen MA, van't Wout AB: Predicting HIV-1 coreceptor usage with sequence analysis. AIDS Rev. 2003, 5: 104-112.

    PubMed  Google Scholar 

  43. 43.

    Pillai S, Good B, Richman D, Corbeil J: A new perspective on V3 phenotype prediction. AIDS Res Hum Retroviruses. 2003, 19: 145-149. 10.1089/088922203762688658.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Brumme ZL, Dong WW, Yip B, Wynhoven B, Hoffman NG, Swanstrom R, Jensen MA, Mullins JI, Hogg RS, Montaner JS, Harrigan PR: Clinical and immunological impact of HIV envelope V3 sequence variation after starting initial triple antiretroviral therapy. Aids. 2004, 18: F1-9. 10.1097/00002030-200403050-00001.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Rozera G, Abbate I, Bruselles A, Vlassi C, D'Offizi G, Narciso P, Chillemi G, Prosperi M, Ippolito G, Capobianchi MR: Massively parallel pyrosequencing highlights minority variants in the HIV-1 env quasispecies deriving from lymphomonocyte sub-populations. Retrovirology. 2009, 6: 15-10.1186/1742-4690-6-15.

    PubMed Central  Article  PubMed  Google Scholar 

  46. 46.

    Borggren M, Repits J, Kuylenstierna C, Sterjovski J, Churchill MJ, Purcell DF, Karlsson A, Albert J, Gorry PR, Jansson M: Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-1 variants emerging during AIDS progression. Retrovirology. 2008, 5: 28-10.1186/1742-4690-5-28.

    PubMed Central  Article  PubMed  Google Scholar 

  47. 47.

    Koning FA, Kwa D, Boeser-Nunnink B, Dekker J, Vingerhoed J, Hiemstra H, Schuitemaker H: Decreasing sensitivity to RANTES (regulated on activation, normally T cell-expressed and -secreted) neutralization of CC chemokine receptor 5-using, non-syncytium-inducing virus variants in the course of human immunodeficiency virus type 1 infection. J Infect Dis. 2003, 188: 864-872. 10.1086/377105.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Fischer M, Joos B, Niederost B, Kaiser P, Hafner R, von Wyl V, Ackermann M, Weber R, Gunthard HF: Biphasic decay kinetics suggest progressive slowing in turnover of latently HIV-1 infected cells during antiretroviral therapy. Retrovirology. 2008, 5: 107-10.1186/1742-4690-5-107.

    PubMed Central  Article  PubMed  Google Scholar 

  49. 49.

    Cicala C, Arthos J, Censoplano N, Cruz C, Chung E, Martinelli E, Lempicki RA, Natarajan V, VanRyk D, Daucher M, Fauci AS: HIV-1 gp120 induces NFAT nuclear translocation in resting CD4+ T-cells. Virology. 2006, 345: 105-114. 10.1016/j.virol.2005.09.052.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Cicala C, Arthos J, Martinelli E, Censoplano N, Cruz CC, Chung E, Selig SM, Van Ryk D, Yang J, Jagannatha S, et al: R5 and X4 HIV envelopes induce distinct gene expression profiles in primary peripheral blood mononuclear cells. Proc Natl Acad Sci USA. 2006, 103: 3746-3751. 10.1073/pnas.0511237103.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  51. 51.

    Kinter AL, Umscheid CA, Arthos J, Cicala C, Lin Y, Jackson R, Donoghue E, Ehler L, Adelsberger J, Rabin RL, Fauci AS: HIV envelope induces virus expression from resting CD4+ T cells isolated from HIV-infected individuals in the absence of markers of cellular activation or apoptosis. J Immunol. 2003, 170: 2449-2455.

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Trushin SA, Algeciras-Schimnich A, Vlahakis SR, Bren GD, Warren S, Schnepple DJ, Badley AD: Glycoprotein 120 binding to CXCR4 causes p38-dependent primary T cell death that is facilitated by, but does not require cell-associated CD4. J Immunol. 2007, 178: 4846-4853.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    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. 10.1172/JCI11109.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  54. 54.

    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  Article  PubMed  Google Scholar 

  55. 55.

    Espert L, Denizot M, Grimaldi M, Robert-Hebmann V, Gay B, Varbanov M, Codogno P, Biard-Piechaczyk M: Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4. J Clin Invest. 2006, 116: 2161-2172. 10.1172/JCI26185.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  56. 56.

    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  Article  PubMed  Google Scholar 

  57. 57.

    Ameisen JC, Capron A: Cell dysfunction and depletion in AIDS: the programmed cell death hypothesis. Immunol Today. 1991, 12: 102-105. 10.1016/0167-5699(91)90092-8.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Banda NK, Bernier J, Kurahara DK, Kurrle R, Haigwood N, Sekaly RP, Finkel TH: Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J Exp Med. 1992, 176: 1099-1106. 10.1084/jem.176.4.1099.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Westendorp MO, Frank R, Ochsenbauer C, Stricker K, Dhein J, Walczak H, Debatin KM, Krammer PH: Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature. 1995, 375: 497-500. 10.1038/375497a0.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Newell MK, Haughn LJ, Maroun CR, Julius MH: Death of mature T cells by separate ligation of CD4 and the T-cell receptor for antigen. Nature. 1990, 347: 286-289. 10.1038/347286a0.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    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  Article  PubMed  Google Scholar 

  62. 62.

    Clem RJ, Fechheimer M, Miller LK: Prevention of apoptosis by a baculovirus gene during infection of insect cells. Science. 1991, 254: 1388-1390. 10.1126/science.1962198.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, Smith K, Lisziewicz J, Lori F, Flexner C, et al: Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999, 5: 512-517. 10.1038/8394.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, et al: Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy [see comments]. Science. 1997, 278: 1295-1300. 10.1126/science.278.5341.1295.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Wong JK, Hezareh M, Gunthard HF, Havlir DV, Ignacio CC, Spina CA, Richman DD: Recovery of replication-competent HIV despite prolonged suppression of plasma viremia [see comments]. Science. 1997, 278: 1291-1295. 10.1126/science.278.5341.1291.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, Lloyd AL, Nowak MA, Fauci AS: Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci USA. 1997, 94: 13193-13197. 10.1073/pnas.94.24.13193.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  67. 67.

    Venkatachari NJ, Buchanan WG, Ayyavoo V: Human immunodeficiency virus (HIV-1) infection selectively downregulates PD-1 expression in infected cells and protects the cells from early apoptosis in vitro and in vivo. Virology. 2008, 376: 140-153. 10.1016/j.virol.2008.03.015.

    CAS  Article  PubMed  Google Scholar 

  68. 68.

    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  Article  PubMed  Google Scholar 

  69. 69.

    Francois F, Klotman ME: Phosphatidylinositol 3-kinase regulates human immunodeficiency virus type 1 replication following viral entry in primary CD4+ T lymphocytes and macrophages. J Virol. 2003, 77: 2539-2549. 10.1128/JVI.77.4.2539-2549.2003.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  70. 70.

    Balabanian K, Harriague J, Decrion C, Lagane B, Shorte S, Baleux F, Virelizier JL, Arenzana-Seisdedos F, Chakrabarti LA: CXCR4-tropic HIV-1 envelope glycoprotein functions as a viral chemokine in unstimulated primary CD4+ T lymphocytes. J Immunol. 2004, 173: 7150-7160.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Poznansky MC, Olszak IT, Foxall R, Evans RH, Luster AD, Scadden DT: Active movement of T cells away from a chemokine. Nat Med. 2000, 6: 543-548. 10.1038/75022.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Wu Y, Yoder A, Yu D, Wang W, Liu J, Barrett T, Wheeler D, Schlauch K: Cofilin activation in peripheral CD4 T cells of HIV-1 infected patients: a pilot study. Retrovirology. 2008, 5: 95-10.1186/1742-4690-5-95.

    PubMed Central  Article  PubMed  Google Scholar 

Download references


This work was supported by Public Health Service grant AI069981 from NIAID to YW.

Author information



Corresponding author

Correspondence to Yuntao Wu.

Additional information

Competing interests

The author declares that he has no competing interests.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Cite this article

Wu, Y. The co-receptor signaling model of HIV-1 pathogenesis in peripheral CD4 T cells. Retrovirology 6, 41 (2009).

Download citation


  • Human Immunodeficiency Virus
  • Human Immunodeficiency Virus Infection
  • Human Immunodeficiency Virus Disease
  • Human Immunodeficiency Virus Replication
  • Human Immunodeficiency Virus Envelope