A cure for AIDS: a matter of timing?
© Shytaj and Savarino; licensee BioMed Central Ltd. 2013
Received: 13 October 2013
Accepted: 12 November 2013
Published: 22 November 2013
Despite the huge clinical success of antiretroviral therapy, several factors such as side effects, requirement of life-long adherence, high cost, incomplete access to therapies and development of drug resistance make the quest for an ultimate cure of HIV/AIDS a worldwide priority of biomedical research. In this respect, several sterilizing or functional cures have been reported in the last years in both non-human primates and humans. This review provides a summary of the main results achieved so far, outlining their strengths as well as their limitations. A synthetic interpretation of these results could be pivotal in order to develop an effective and widely available cure.
KeywordsEradication Functional cure Reservoirs Acute HIV infection Stem cell transplantation Vorinostat Therapeutic vaccine Auranofin BSO
The quest of a cure for AIDS has been defined a “herculean task” , given the enormous complexities behind it and the numerous setbacks that have curbed early enthusiasms along the years. The ultimate goal of research for a cure is the complete eradication of the virus from the organism (i.e. a “sterilizing cure”), but a more feasible goal may be the achievement of spontaneous drug-free control of the infection without disease progression (i.e. a functional cure) . The enormous difficulties that have been encountered in the quest of a cure for AIDS reside in the complex virus/host interplay that is a hallmark of this disease. Infection with HIV is initially characterized by a primary (acute) phase in which the virus is partially controlled by a robust immune response of the host . Unfortunately, this immune response is not sufficient to eradicate the virus from the body, opening the way to the asymptomatic (chronic) phase. The chronic phase is characterized by an initial “steady state” between the virus and the immune system that is then slowly tilted in favor of the former, eventually leading to AIDS in the majority of the patients . Treatment with antiretroviral drugs (ART) can reproducibly decrease viremia to levels below the limit of detection of the routine clinical assays and delays immune deterioration, but is not sufficient to tackle the viral reservoirs or to induce a strong immune response against the virus [5–7]. The viral reservoirs are formed early during acute infection  and are exceptionally stable sources of viral persistence [6, 9], harboring latent copies of integrated virus that are “invisible” to the immune system and unharmed by ART (5,6,9, for a review on the latency mechanisms, see: ). Viral reservoirs can be of both myeloid and lymphoid lineage, allowing a widespread distribution to different compartments such as the central nervous system, the gut-associated lymphoid tissue and the reproductive tract . At a cellular level, central and transitional memory T-cells (TCM and TTM) were recently identified as a crucial source of viral persistence during therapy . Additionally, macrophages are regarded as important contributors to this persistence, as well .
This review provides an outline of the therapeutic successes in the pathway towards a cure for AIDS. Our description is focused on the results that have so far been obtained in humans or SIV/SHIV infected macaques, which are, among the allowed animal models, those phylogenetically nearest to humans and most closely recapitulating the pathogenesis of human AIDS [14, 15]. Recent reports have provided substantial data supporting the view that the path to a cure is a viable research avenue. These new data allow attempting a re-evaluation of the paradigms that have oriented cure-related research and addressing some of the questions that have so far been left unanswered.
Hit fast, hit hard
Acute infection offers an ideal time window for effective therapeutic interventions . A pioneering demonstration of the therapeutic potential of early treatment was the case report of spontaneous control of viral replication following treatment interruption in the first “Berlin Patient”  (not to be confused with Mr. Timothy Brown, the second “Berlin Patient”, see next subchapter). This man was treated during acute infection with a non-standard ART regimen (containing hydroxyurea) and subsequently underwent two structured treatment interruptions (STI). Eventually, after the second STI, the man displayed a long-lasting (19 months, until he was lost to follow-up) spontaneous control of viral load below the assay detection limit (500 copies of viral RNA/mL). Moreover, viral load control was accompanied by immune restoration, with CD4 counts and CD4/CD8 ratio progressively increasing over time . This striking result confirmed those of a previous study by Vila et al., employing a similar drug regimen and achieving as well a long-lasting post-therapy viral load control in two human subjects . However, both studies were uncontrolled, and the two clinical cases described by Vila et al. were associated with high CD4 counts and low viral loads before treatment initiation . A fully controlled animal study employing a therapy containing hydroxyurea administered sequentially in the form of multiple ART/STI cycles strengthened these case reports and showed that post-therapy viral load control could be induced in macaques acutely infected with the HIV homolog SIVmac251 . Of note, in all these studies, apart from the early treatment initiation, hydroxyurea may have played a role in the post-therapy viral load control obtained. Hydroxyurea exerts a cytostatic effect by inhibiting the activity of the ribonucleotide reductase enzyme, thus halting the cell cycle at the G1 phase . This effect may hamper viral reservoir maintenance/expansion in TCM and TTM cells that mainly relies on antigen-driven and homeostatic proliferation respectively . Despite these promising results, combinations of hydroxyurea and antiretroviral drugs displayed in some instances high pancreatic and hepatic toxicity [20, 21] and consequently hydroxyurea is not recommended for routine treatment of HIV infection, although there is still ongoing research on this topic .
Another uncommon ART regimen administered during early infection yielded promising results in a recent study conducted in macaques infected with different SIV/SHIV strains . In some of these animals, a prolonged (more than 8 years) tenofovir monotherapy proved able to induce a spontaneous control of the infection following the final treatment withdrawal . Apart from the early treatment initiation, this result may be due to an effect of tenofovir in selecting suboptimal drug resistance mutations, and the result may also have been contributed by the additional interventions to which the macaques were subjected during follow-up (temporary depletion of CD8+ cells and treatment at viral rebound).
Treatment during acute infection has provided some amount of clinical success also with more traditional ART regimens [24–30]. News such as the case report of the cure of an ostensibly HIV+ baby treated in the very early phase of the disease  and, more importantly, the results of the ANRS VISCONTI study  have been hailed with widespread enthusiasm. Of particular note, up to ≈ 15% of the early treated individuals have been shown to display spontaneous control of viremia following STI . However, the rate of post-therapy control following ART administration during the acute phase may be lower (≈5%) according to another report . Moreover, no definite timing and drug composition has been proven to reproducibly induce post-therapy control even in a minority of patients, and several studies have failed to induce any significant reduction in the post-therapy viral set point following treatment during acute infection [31–33].
Hit later, hit harder
The mainstream approach to purge the viral reservoirs during chronic infection is a multi-step “shock and kill” therapy . During the “shock” phase, the latent virus harbored in the reservoirs is expected to be pharmacologically reactivated and prompted to resume productive infection. During the”kill” phase, the newly produced virions would be blocked by ART, while the HIV-infected cells are expected to be eliminated by viral cytopathogenicity, or recognized and killed by the immune system. A plethora of compounds have been put forward as candidates to induce the “shock” phase (recently reviewed in: [45, 46]). Among these, the most thoroughly investigated are histone deacetylase inhibitors (HDACI’s). Several HDACI’s (e.g. valproic acid, vorinostat, panobinostat) have been tested or are currently under investigation in both pre-clinical studies and clinical trials (reviewed in: ). Vorinostat [i.e. suberoylanilide hydroxamic acid (SAHA)] was recently reported to have a moderate latency disrupting effect in a group of patients previously selected for the responsiveness of their resting CD4+ memory T-cells to treatment with this drug in vitro. However, preliminary data do not show significant effects of vorinostat on viral reservoir size [49, 50], while no data on post-therapy viral dynamics are available so far. Moreover, treatment with combined ART/vorinostat regimens on SIVmac-infected macaques led to mixed or disappointing results [51, 52]. More data on the in-vivo effects of vorinostat will be available from the two ongoing clinical trials investigating the effects of this drug on individuals under ART (NCT01319383, NCT01365065). For the remaining HDACI’s only data obtained from cell cultures are available at present [53–55], although panobinostat is currently under investigation in a Phase I/II clinical trial (NCT01680094).
Another approach aimed at HIV reactivation from latency involves the use of cytokines (reviewed in ). In particular, the use of IL-7 in combination with ART intensification is currently being investigated (NCT01019551). Unfortunately, in two recent clinical trials, the addition of IL-7 to standard ART protocols did not result in viral reactivation from latency , and increased the size of the viral reservoir , in line with the well-known effects of this cytokine, favoring homeostatic proliferation of TCM and TTM cells [12, 58, 59].
Despite the enormous efforts that have been put in the study of HIV reactivating HDACI’s and cytokines, the most promising results so far obtained in the quest of a cure for AIDS are not derived from these approaches. The most astonishing result in the field to date, and the first proof of concept for the feasibility of a sterilizing cure during chronic HIV infection, is the case report of the treatment of Mr. Timothy Brown, the aforementioned second “Berlin Patient” [60, 61]. Apart from being chronically infected with HIV, this man was diagnosed with acute myeloid leukemia and consequently treated with an aggressive combination of ablative chemotherapy/radiotherapy, immune suppression through drugs and allogeneic stem cell transplantation. Importantly, the donor selected for the transplantation was homozygous for the Δ32 deletion of the CCR5 gene . This gene encodes for the main coreceptor employed by HIV for entry into cells, and individuals homozygous for the Δ32 deletion (about 1% of the caucasian population) are protected from HIV infection . Following stem cell transplantation, Mr. Brown stopped taking antiretroviral drugs, and has remained off-ART since then, with no signs of disease progression [60, 61]. Of note, in spite of an extensive sampling throughout the years, most of the analyses have failed to detect HIV RNA or DNA in blood and tissues, and the HIV-specific antibody titers have steadily decreased over time, thus hinting that a complete eradication may have been achieved [61, 63]. Despite the enormous excitement generated by the news of this cure, the scarcity of HLA-DR-compatible CCR5 Δ32 donors makes it very difficult to replicate the whole experiment. Consequently, several attempts have been made to isolate the contribution of each of the different therapy components. Allogeneic bone marrow transplantation had been employed for treatment of HIV since the first years of the epidemics (reviewed in ) and had been even advocated as a possible curing strategy . The most visible difference between these early attempts and the treatment of Timothy Brown is the favorable genetic background of the cells received by the latter, bearing the homozygous CCR5 Δ32 deletion. Thus, it is not surprising that many investigators have used this observation as a starting point for further studies. In this regard, a gene therapy approach aimed at disrupting the CCR5 gene (virtually recreating the Δ32 deletion) is currently under investigation in clinical trials (NCT01252641, NCT00842634). In these studies, the disruption of CCR5 is performed employing zinc finger nucleases in previously isolated autologous cells that are afterwards re-transplanted in the host. The preliminary results released so far do not allow drawing a definite conclusion on post-therapy viral load dynamics, which seem to be quite variable among study subjects, although post-therapy viral load containment may have been achieved in a small subset of individuals that were heterozygous for CCR5 Δ32 at baseline . Anyway, the zinc finger treated CD4+ T-cells have been shown to be able to persist in the organism at least one year after the transplant and have had an enhancing effect on CD4 counts in immunologic non-responders .
Turning back time
Immune enhancement: rejuvenating the immune system?
Enormous efforts have been put in the development of strategies able to boost antibody and/or cell-mediated immune responses against HIV (reviewed in ). The curative potential of broad and robust cell-mediated immune responses, in particular by CD8+ T-cells, is suggested by the association of such responses with better disease progression resulting in spontaneous drug-free control of viral load in a minority of individuals [76–79]. Thus, drugs able to bolster immunity against HIV-infected cells could represent an ideal tool for prompting, or supporting, a spontaneous control of the infection . A promising compound for enhancing cell-mediated immune responses against HIV may be buthionine sulfoximine (BSO), a glutathione-depleting agent previously tested for cancer treatment in phase I clinical trials . We recently showed that the addition of BSO to the aforementioned ART/auranofin combination is able to promote a significant and long-lasting enhancement of specific immune responses directed against SIVmac Gag . Boosting immunity against Gag is an attractive achievement because several studies have shown that strong anti-Gag immune responses are associated with low viral loads and high CD4 counts both in macaques and humans [82–86]. Moreover, the results of a recent study suggest that CD8+ T-cells may reduce the viral reservoir by recognizing Gag antigens produced by latently infected resting CD4+ T-cells . In accordance with these studies, enhancement of the immune responses against Gag following suspension of treatment with ART/auranofin/BSO was associated with the obtainment of a functional cure-like condition in a study conducted on a small number of chronically SIVmac251-infected macaques .
Partially similar results were obtained using a therapeutic vaccine based on dendritic cells pulsed with whole inactivated virus [88–91]. This vaccine proved able to achieve drug-free control of viral load in a subset of chronically SIVmac251-infected macaques  and to induce a reduction of viral load, although moderate, in ART-naïve HIV+ subjects [89, 90]. Moreover, coupling the vaccine administration to ART induced a reduction in post-therapy viral load set point in some individuals . Of note, the highest viral load reductions observed in ART-naïve subjects were associated with high numbers of Gag-specific CD8+ T-cells .
A proof-of-concept that strong CD8+ (in particular TEM)-mediated immune responses can even lead to viral eradication was recently furnished by a preventive vaccine study conducted on macaques challenged with SIVmac239 . Despite all vaccinated macaques becoming infected following multiple challenges with the virus , about half of them proved able to spontaneously control the infection and, strikingly, to get rid of the virus completely in the long run . Interestingly, an involvement of TEM cells was also shown, by multiple correlation analysis, in the effects of the auranofin-based therapeutic approach .
On the other hand, antibody-mediated immune responses have also proven the ability of inducing post-therapy viral load control [94, 95]. In particular, in the recent study of Barouch et al., a cohort of SHIV(env)-infected macaques was treated with wide spectrum neutralizing antibodies . This treatment produced a functional cure in those macaques starting from viral loads of less than 3.5 Log10 viral RNA copies/mL of plasma . Of note, this experiment provides an artificial substitution of a “non-functional” immune system with a surrogate functional immunity, i.e. the passive antibody transfer. The capability of adoptive antibody transfer to induce a functional cure only in those macaques displaying low baseline viral set points, supports the view that a limited viral reservoir should accompany the immune system renovation.
Finally, also the effects of transplantation strategies on viral load control may be associated with enhancement of immune responses. A study by Villinger et al. conducted in chronically SIVmac239-infected macaques showed that adoptive transfer of activated autologous CD4+ T-cells may result in spontaneous post-therapy control of the infection . This approach can hardly be employed in humans since it requires cells isolated before the infection, but it suggests that renovation of the immune system is important for obtaining effective immune responses . Of note, autologous stem cell transplantation did not result in a cure of HIV+ individuals , suggesting that cells isolated following infection may not be apt to prompt immune enhancement. Instead, the likely cures observed following allogeneic transplantation in the “Boston patients”  may have been induced or facilitated by the strong immune responses resulting from graft versus host disease, exacerbated by a partial HLA donor/receiver mismatch in one of the two patients, which may have played a critical role for the elimination of the viral reservoirs .
Summary of the main characteristics of the therapeutic strategies described in this review
ART during acute infection
Low (few patients are detected HIV+ at acute infection)
Viral reactivation with HDACI’s
Viral reactivation with cytokines
Gene therapy for disruption of CCR5
Medium (long-term effects unknown)
Allogeneic stem cell transplant
Addition of auranofin and BSO to ART
Medium/high (good safety profile for individual drugs in humans)
Therapeutic vaccine with whole virus-pulsed dendritic cells
Administration of broadly neutralizing antibody/ies
Long-term post-therapy control in chronically SHIV(env) infected macaques starting from low viral loads 
Structured treatment interruption
Histone deacetylase inhibitor
Simian immunodeficiency virus
Simian/human immunodeficiency virus
T central memory
T transitional memory
T effector memory.
The authors are thankful to Dr. Marco Sgarbanti for critically reading the manuscript and for providing helpful suggestions.
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