Marys Medicine

Hiv cure research_ advances and prospects

Contents lists available at journal homepage: HIV cure research: Advances and prospects Caroline P. Passaes ,, Asier Sáez-Cirión a Unité de Régulation des Infections Rétrovirales, Institut Pasteur, 25–28 rue du Dr Roux, 75724 Paris Cedex 15, Franceb CEA, Division of Immuno-Virology, iMETI/DSV, 18 Route du Panorama, 92265 Fontenay-aux-Roses, France Thirty years after the identification of HIV, a cure for HIV infection is still to be achieved. Advances of Received 14 February 2014 combined antiretroviral therapy (cART) in recent years have transformed HIV infection into a chronic Returned to author for revisions disease when treatment is available. However, in spite of the favorable outcomes provided by the newer therapies, cART is not curative and patients are at risk of developing HIV-associated disorders. Moreover, Accepted 20 February 2014 universal access to antiretroviral treatment is restricted by financial obstacles. This review discusses the Available online 11 March 2014 most recent strategies that have been developed in the search for an HIV cure and to improve life quality of people living with HIV.
& 2014 Elsevier Inc. All rights reserved.
EradicationRemission of HIV infectionHIV reservoirsReactivation of latent virusRepression of provirusControl of infection avoiding drug resistance and side effects. Due to advances inantiretroviral development, HIV infection can nowadays be handled The introduction of improved combined antiretroviral therapy as a complex chronic disease ). Nonetheless, (cART) has dramatically improved the clinical outcome and life despite all of the clinical benefits provided by drug therapy, cART expectancy of HIV infected patients. The development of drugs that alone is not able to eradicate the virus, which persists in reservoirs inhibit different steps of viral replication allows clinicians to success- that are thought to be the source for viral reemergence after fully manage the disease, improving immunologic parameters, and treatment interruption (). Inaddition, cART does not fully restore health – it increases the risk ofnon-AIDS disorders such as cardiovascular, kidney, liver and neuro-logical diseases. Moreover, persistent immune dysfunction and n Corresponding author. Tel.: þ33 145 688 944; fax: þ33 145 688 957.
inflammation increase the risk of non-AIDS morbidity and mortality E-mail addresses: (C.P. Passaes), . Sáez-Cirión).
0042-6822 & 2014 Elsevier Inc. All rights reserved.
C.P. Passaes, A. Sáez-Cirión / Virology 454-455 (2014) 340–352 a cure for HIV infection is needed to bypass the limitations of the Is a cure for HIV possible? current therapy and restore health. Although a vaccine against HIVremains an unachieved aspiration, several recent findings suggest Since the isolation and characterization of the HIV as the that either a cure or a durable remission of infection might be etiologic agent of AIDS (the search for a cure has been considered a major research priority. The Berlin patient
Radio/chemotherapy
Total body irradiation
Detectable viremia
Boston patient A
Boston patient B
Fig. 1. Schematic representation of the clinical course before and after allogeneic hematopoietic stem cell transplantation (HSCT) in the Berlin (A) and the Boston patients(B and C) as described in and . The most important events associated to the HSCT and HIV disease are indicated. Blue arrowsrepresent the periods of radio/chemotherapy. Red arrows represent total body irradiation. Periods of detectable viremia are represented by orange boxes. The period thatpatients were under antiretroviral treatment are indicated in grey below the timeline. The period between allogeneic HSCT and ATI in Boston patients are indicated bybrackets. AML: acute myeloid leukemia; ATI: analytical treatment interruption; cART: combined antiretroviral therapy; HL: Hodgkin lymphoma; HSCT: hematopoietic stemcell transplantation; GVHD: graft-versus-host disease; WT: wild type.
C.P. Passaes, A. Sáez-Cirión / Virology 454-455 (2014) 340–352 description of a unique case of HIV cure after hematopoietic stem and/or lymphomas ). Nevertheless, in most of these studies cell (HSC) transplantation has boosted remarkable optimism in the HIV was detected after transplantation, either following therapy field and rekindled the hope that a cure for HIV infection is withdrawal or because the therapeutic regimen was not able to possible. In 2007, the so-called "Berlin patient" – HIV positive and completely eliminate the viral reservoirs. In addition, in several cases, diagnosed with acute myeloid leukemia – received double allo- the patients died after transplantation. The most recent study geneic HSC transplant from an HLA-matched and unrelated donor investigating the impact of cART on viral reservoirs in two patients screened for homozygosity for the CCR5 Δ32 allele ( who received HSC transplantation – known as "the Boston patients" This patient discontinued ART the day before the first – described an important reduction of HIV DNA in long term, transplantation and, after 6 years of follow up in the absence of reaching undetectable levels . These observa- therapy, he shows no trace of HIV in blood and tissue samples tions are in agreement with another study which described that HIV (revealing no evidence for persistent HIV. Levels of HIV- DNA levels at month 24 post transplantation in HSC transplanted specific antibodies have also declined, suggesting that HIV antigen patients are lower than those observed at baseline stimulation was very low or absent after transplantation Altogether, these data suggest that HSC transplantation in association with cART may reduce viral reservoirs in HIV infected Several studies have aimed to use autologous or allogeneic HSC patients. However, a recent report during the 6th International transplantation in association with antiretroviral therapy as a strategy Workshop on HIV Persistence, Reservoirs and Eradication Strategies to eradicate HIV in seropositive patients diagnosed with leukemia revealed that the Boston patients experienced a strong rebound in Table 1Hematopoietic stem cell transplantation in HIV positive patients Diagnosis Graft type Strategy against HIV infection Effect on HIV persistence High-dose zidovudine for No detectable HIV RNA and DNA at Death 47 days after 2 weeks before transplantation. day 32 after transplantation and at Lower maintenance dose Zidovudine, IFN-alpha 2 and No detectable HIV RNA at day 30 Death 10 months after anti-HIV-1-specific T cell after transplantation and at autopsy. transplantation.
cART before and after No detectable HIV RNA on cART Alive after 42 months of follow transplantation, with from day 210 after transplantation.
interruptions due to side-effects.
Autologous cART before and after No detectable HIV RNA on cART in Five patients were alive.
three patients who survived.
Autologous cART before and after The four patients were alive No detectable HIV RNA after after 12 months of follow up.
transplantation (two patients),viral load rebound (two patients).
Detectable HIV DNA at month 12after transplantation for allpatients.
cART before and after Undetectable RNA and DNA on cART. Death 191 days after transplantation, with Detectable HIV RNA and DNA at day transplantation.
interruptions due to side- 16 after TI.
Donor homozygous for CCR5 No cART. No trace of HIV after Alive after 6 years of follow up.
6 years of follow-up.
Considered the first case of Autologous cART before and after Alive, immunologic transplantation, with Detectable HIV RNA and DNA after characteristics comparable to interruptions due to side- HIV negative patients.
effects (n¼8).
HIV DNA significantly lower atmonth 24 than those at baseline.
Autologous cART before and after Alive with undetectable VL by transplantation, with Detectable HIV RNA (9/10 conventional methods, but with interruptions due to side- patients) and DNA (10/10 detectable proviral DNA.
effects (n¼3).
patients) after transplantation.
cART before and after Undetectable HIV RNA on cART, Alive 5 and 3 years after detectable after TI.
transplantation, but viremia Detectable HIV DNA early after rebounded after TI.
transplantation and undetectablein long term follow-up.
Donor homozygous for CCR5 No detectable HIV after treatment Died 2 months after Δ32 deletion.
transplantation by a severe ALL: acute lymphoblastic leukemia; AML: Acute myeloid leukemia; BL: Burkitt lymphoma; BM: bone marrow; F: Female; HL: Hodgkin lymphoma; M: male; NHL: non-Hodgkin lymphoma; NA: not available; PBMC: Peripheral blood mononuclear cells; PCR: polymerase chain reaction; TI: treatment interruption; VL: viral load.

C.P. Passaes, A. Sáez-Cirión / Virology 454-455 (2014) 340–352 plasma viremia several months after analytic treatment interruption (1% of caucasians) (), what makes the search for a (ATI) and C) (http://es.scribd.com/doc/189931630/12-06-13- compatible donor with the protective genotype an additional suggest that HIV hides in yet unidentified sanctuaries or at levelsthat are not detectable by current available techniques.
So far, HSC transplantation to eradicate the virus was success- How can HIV infected patients achieve durable remission of ful only in the Berlin patient. The mechanisms involved in HIV eradication in this patient are not yet fully understood. Thispatient underwent severe particular transplant conditions "HIV controllers" or "elite controllers" correspond to a small (), such as double HSC transplantation percentage of HIV infected patients that can naturally control viral from the same CCR5 Δ32 donor, conditioning regimen (total body replication below the levels of detection with standard clinical irradiation) and the development of graft-versus-host disease assays. Consequently, this group of patients is considered an (GVHD), which may have contributed to cure. Comparison with important model to understand the mechanisms underlying con- the protocols applied in the case of the Boston patients trol of infection in the absence of treatment ( ) suggests that total body irradiation or the engraft- The aim of a so-called "functional ment with cells from a CCR5 Δ32 donor may have been critical cure" would be similarly to HIV controllers, that is, to allow HIV differential aspects in the case of the Berlin patient. As the infected patients to achieve viral remission in which HIV remains homozygous CCR5 Δ32 deletion offers a natural resistance to in the body at low levels and it is controlled by the host in the HIV infection ), this unique successful experi- absence of cART. This status may be achieved by 5–15% of patients ence has encouraged the search for new CCR5-based therapeutic treated very early during primary HIV infection (PHI) for long approaches for HIV cure interventions (see below). It is interest- periods of time who experience treatment interruption afterwards ing to notice that the Berlin patient and both Boston patients were originally heterozygous for the CCR5 Δ32 allele, but this did not confer any advantage to the Boston patients once treatment These patients are known as "post- was interrupted (A recent effort to cure HIV infection in a 12-year old boy with acute The VISCONTI study (Viro-Immunological Sustained CONtrol after lymphoblastic leukemia consisted of an allogenic transplantation Treatment Interruption) investigated whether the characteristics of of HSC obtained from cord blood. Similar to the Berlin patient, the 14 post-treatment controllers were similar to those observed in HIV donor was screened for homozygosity for the CCR5 Δ32 allele.
controllers that spontaneously control HIV replication ( This procedure was performed at the University of Minnesota in In this study, cART duration after primary infection was April 2013, but the pediatric patient died two months after 3 years, and after treatment interruption, post-treatment controllers transplantation by a severe GVHD ( presented a sustained control for a median of 7 years. During acute phase, post-treatment controllers had higher viremia levels and lower CD4þ T cell counts than patients who naturally control Despite the impact of HSC transplantation on reducing HIV infection afterwards. In addition, these groups of patients have a reservoirs, this kind of treatment is not a viable option for the different genetic background – while HIV controllers cohorts are majority of HIV infected patients, since it is a risky and expensive enriched by the protective HLA-B27 and B57 procedure that is recommended only for those who develop the risk alleles B07 and cancer. Furthermore, CCR5 Δ32 homozygous donors are rare Fiebig I-III
Fiebig IV-V
infection
Naive TCM
HIV Reservoir
(T cell subsets)
Days after HIV infection
Fig. 2. Schematic representation of the HIV acute infection and the contribution of each T cell subset to the establishment of the HIV reservoir. Early treatment during Fiebigstages I–III may limit the number of infected cells and protect TCM cells from infection. Treatment during Fiebig stages IV-V may decrease the contribution of long-lived TNand TCM cells to the reservoir due to low relative abundance of these cell subsets. Frequency of TCM normalizes during chronic infection increasing the contribution of thesecells to the reservoir.
C.P. Passaes, A. Sáez-Cirión / Virology 454-455 (2014) 340–352 were prevalent among the 14 post-treatment additional studies will be needed to understand the mechanisms controllers. HIV-1 specific CD8þ T cell responses and immune that may lead to a long-lasting viral remission in post-treatment activation differ between post-treatment controllers and HIV con- trollers (post-treatment controllers have weak CD8þ T cell responsesand a low level of immune activation during the control phase).
Another recent incident that suggests that a very early treat- Is it better if we intensify ART? ment may lead to HIV remission is the case identified as "theMississipi baby" (This infant born to a Therapeutic intervention during PHI appears to be valuable seropositive mother started receiving cART 30 h after birth. HIV- in inducing viral remission in a certain number of HIV infected 1 RNA was detectable at 31 h, days 6, 11 and 19, and reached patients. However, just a small percentage of patients are diag- undetectable levels at day 29. cART was discontinued sometime nosed during PHI. Most of them will know their seropositive status between months 18 and 23. At 36 months of age and after therapy only during the chronic phase of HIV infection. For the great withdrawal, HIV-1 RNA, proviral DNA and HIV-1 antibodies remain majority of HIV infected patients, other strategies to achieve viral consistently undetectable or extremely low in blood and tissues in remission must be developed. Combined antiretroviral therapy this pediatric patient.
dramatically reduces viremia to levels below the detection limit of The study of post-treatment controllers may give valuable current assays ( o50 copies/mL), but low-level residual viremia information to guide the search for a successful strategy for persists and is usually detectable by ultra-sensitive tests in inducing viral remission. However, some open questions remain.
patients undergoing successful ART ). Residual For instance: which are the mechanisms underlying control? and viremia may partially be the cause of persistent immune activation how can we increase the probability of HIV infected patients to ), which increases the risk of non-AIDS become a post-treatment controller? Recent studies suggest that morbidity and mortality in treated patients both the timing to initiate therapy (; There are two probable sources of residual viremia (i) long-lived, latently and the duration of cART () infected cells whose provirus became transcriptionally active, with might play a key role in the achievement of a durable HIV control.
intermittent or continuous viral release; and (ii) ongoing low- In addition, baseline viral load and immune activation may predict levels of HIV replication with de novo viral infection, due to partial success (). Whether the therapeutic regi- suppression and/or to inadequate drug penetration. In the latter men used during PHI may impact the outcome is still to be case, therapy intensification should reduce the residual viremia investigated. In any case, in the absence of markers predicting and associated persistent inflammation. Moreover, in the long success after treatment interruption, this procedure is not recom- term, it would be expected to decrease HIV reservoir levels.
mended outside structured protocols for patients undergoing Previous studies of therapy intensification with protease and suppressive cART.
reverse transcriptase inhibitors were contradictory in determining Treatment during PHI seems to result in broad and strong HIV- whether or not ongoing replication is the source of persistent 1 specific immune responses ( ). The development of new classes of antiretroviral drugs allowed the exploration of the impact of treatment intensification activation (immune restoration in the with drugs targeting other steps of HIV replication cycle. Treatment gastrointestinal mucosa and limited viral intensification with Raltegravir (RAL), a potent integrase inhibitor, evolution Additionally, initiation of offered a unique opportunity to study the dynamic of ongoing low- cART during PHI may limit the establishment of viral reservoirs level replication. As RAL blocks HIV integration, residual replication could be assessed by the increase of 2-LTR circles ( ). Central memory Most studies of RAL treatment intensification showed no impact on CD4 þ T cells (TCM) are a key component of the long-lasting HIV residual viremia, immune activation or in promoting CD4þ T cell reservoir and recent studies have demon- reconstitution. Collectively, these data suggested that residual strated that very early cART limits the seeding of the HIV reservoir viremia does not originate from ongoing cycles of HIV replication in long-lived TCM (Ananworanich et al., 2013. 20th Conference on Retroviruses and Opportunistic Infections, San ). In contrast, the study Francisco, USA). Reservoirs levels in post-treatment controllers of Buzon et al. (identified a transient increase in the levels of during the control phase were very low and it was mostly 2-LTR HIV DNA within two to four weeks after intensification, but associated to the transitional memory CD4 þ T cell subset, due to no significant decrease in low-level viremia was observed. In a skewed distribution of quiescent CD4 þ T cell subsets in these addition, only those patients with high levels of immune activation at baseline presented a decrease in these markers. These findings Treatment interruption in patients who started cART during strongly suggested that RAL intensification was blocking new chronic phase leads to viral rebound within weeks, with viral loads rounds of infection in these patients and that consequently ongoing frequently reaching pretreatment set-point levels ( replication was taking place. Nonetheless, other studies failed to detect 2-LTR increase in RAL intensified-treated patients ( Notwithstanding, some patients that started cART during chronic ). It is possible that differences in phase were also described to maintain controlled levels of viremia patients' characteristics, cART regimens at baseline, and/or the time after therapy discontinuation ). For all these of therapy intensification with RAL had an impact in the discre- studies describing cases of a potential "functional cure", long pancies observed among these studies. An important observation in period follow-up is needed to evaluate whether long HIV control the Buzon et al., study was the fact that 61% of the patients with can be maintained and the mechanisms involved in the long-term detectable 2-LTR were taking a protease inhibitor-based regimen suppression after treatment interruption. Collectively, these stu- (PI). More recently, Hatano and colleagues also detected the dies suggest that HIV remission is possible to be achieved with the transient increase of 2-LTR, which was also more accentuated in help of therapeutic interventions in patients without a favorable patients taking PI In addition, a significant genetic background to naturally control HIV infection. Certainly, reduction in D-Dimer levels, a coagulation biomarker, was observed, C.P. Passaes, A. Sáez-Cirión / Virology 454-455 (2014) 340–352 indicating that RAL intensification may lead to reduction in inflam- had many undesirable effects, associated with exacerbated immune activation and cytokine release, induction of anti-OKT3 Because HIV-1 might replicate in tissue reservoirs where drug antibodies and severe long-lasting depletion of CD4 þ T cells concentrations are suboptimal (such as lymph nodes, gut associated lymphoid tissues, bone marrow and HDAC inhibitors were next proposed as optimal candidate to the central nervous system, some RAL intensification studies flush HIV reservoirs due to their potential to activate HIV transcrip- assessed the immunologic and virologic responses in tissues. Yukl tion without inducing generalized immune activation. Chromatin et al., showed reduction in unspliced HIV RNA, T cell activation and condensation is regulated by the level of acetylation/deacetylation a trend towards CD4 þ T cell increases in ileum, suggesting that of the histones that constitute the core of the nucleosomes. Histone this tissue may be an important site for ongoing replication in acetyl transferases (HAT) mediate the addition of acetyl groups to some patients on cART ). In contrast, therapy histones, reducing chromatin condensation and promoting tran- intensification with RAL did not impact cerebrospinal viral loads scription. Histone deacetylases (HDAC) remove the acetyl groups or isolated HIV semen shedding ( and repress transcription. The balance of HAT/HDAC activities is thus thought to be a key component of HIV latency. The first Based on previous observations that Maraviroc (MVC), a CCR5 molecule with HDAC inhibitory activity to be assayed in vivo was antagonist, promotes a gain of CD4þ T cells in viremic HIV-infected valproic acid (VPA). A first study reported a decrease in the patients it was hypothesized frequency of circulating resting CD4þ T cells carrying replication that the immunomodulatory effects of this drug could decrease competent HIV-1 in four patients receiving cART after 16 weeks of immune activation and improve CD4þ T cell counts in patients under additional treatment with VPA ). However, suppressive cART with insufficient immunological restoration. As subsequent randomized clinical studies could not confirm these observed in RAL intensification trials, no impact in residual viremia results and no significant effects of VPA were evidenced or HIV reservoir was achieved. Data regarding CD4þ T cell gain was also controversial in these trials Failure of VPA was eventually associated to a poor capacity of ). Some unexpected effects, this molecule to inhibit HDAC3, the HDAC isoform that is thought to however, were observed in MVC intensification trials, such as play a preponderant role in HIV latency (). In a increased activation levels in blood and rectal mucosa proof of concept study, the more potent HDAC inhibitor vorinostat increase in plasma LPS, sCD14 and sCD163 has shown capacity to increase levels of HIV mRNA transcripts after ) and increased 2-LTR levels a single dose, without affecting overall HIV DNA cellular levels suggesting that MVC intensification might (). Preliminary results of the NCT01365065 trial induce viral replication. The mechanisms underlying these effects presented in the 20th Conference on Retrovirus and Opportunistic are still unclear, but some evidences suggest that MVC promotes an Infections (.) also reported an increase of cell increase in the circulating levels of CCL3 (MIP-1α), CCL4 (MIP-1β) and associated unspliced HIV mRNAs in 15/17 patients on cART who CCL5 (RANTES), natural ligands of CCR5, which may activate T cells received daily doses of vorinostat for 14 days. Another clinical trial and monocytes/neutrophils through CCR3/CCR4 and CCR1 signaling, (NCT01680094) is evaluating the impact on HIV reservoirs of respectively ). Further studies are panobinostat, which has been described as an even more potent necessary to carefully evaluate the immunomodulatory effects of MVC HDAC inhibitor ().
in vivo and the benefits of therapy intensification with CCR5 antago- The use of HDAC inhibitors in the context of HIV cure face several nists in HIV-infected patients.
hurdles. Among them, the lack of specificity of HDAC inhibitors may Despite some evidence that therapy intensification may have impact the transcription of a large fraction of all cellular genes positive effects on residual replication, its potential to eradicate (). Also, it has been recently shown the virus appears limited. These results highlight the importance that viral reactivation with HDAC inhibitors will not necessarily of designing new strategies to eliminate persistent HIV reservoirs.
be followed by viral-induced cell death, and that immune responsesmay need to be boosted in parallel to recognize and eliminate thesenew viral-producing cells (see below). It is also unlikely that HDAC HIV persistence as a challenge for a cure inhibition by itself will be able to induce efficient viral reactivation inthe absence of the factors necessary to ensure full viral transcription.
HIV replication and persistence depend on the integration of The current belief is that it will be necessary to combine treatment of the viral DNA in the host genome. Although most proviruses HDAC inhibitors with other molecules able to provide the additional integrate in transcriptionally active genomic regions, in most cases stimuli required for HIV transcription. PKC agonists, such as prostra- these proviruses remained repressed Our knowl- tin ) and bryostatin edge of the complex mechanisms underlying establishment and ), or TLR agonists that activate NF-kB maintenance of HIV latency has been enormously improved in the have been proposed as good potential combinatorial candidates.
last years (see for a thorough Purging viral reservoirs is undoubtedly the only solution to review). Repressed HIV proviruses integrated in long-lived cells achieve HIV eradication. However, letting aside the mechanistic constitute the persistent HIV reservoir, which is not recognized by issues, activating every single latently infected cell in the organism immune responses, not eliminated under cART, and is the main still appears a gargantuan endeavor. Taking the example of natural obstacle to achieving an HIV cure. Since the description of HIV HIV controllers or the post-treatment controllers from the VISCONTI reservoirs despite long-term cART, attempts to purge this reservoir study, durable HIV remission may be a more reasonable goal in the have been tried. The first one consisted in the infusion in three medium term. In this setting, limiting and controlling the viral patients under cART of the anti-CD3 OKT3 antibody in the reservoirs would be the main objectives. With this in mind, our presence of IL2, in an effort to mimic in vivo a well-established current knowledge, albeit incomplete, of HIV latency and transcrip- in vitro reactivation protocol ). OKT3 þIL2 tion might be turned to devise strategies aiming to repress, rather treatment was accompanied by very strong activation of T cells, than activate, viral transcription. As alternatives to HDAC inhibitors, and transient increases of HIV RNA levels were observed in plasma HAT inhibitors such as garcinol derivatives ) or lymph nodes of these patients. However, no decrease in the and curcumin have been shown to inhibit HIV frequency of infected cells could be reported and the treatment transcription in vitro. Transcriptional elongation of the viral C.P. Passaes, A. Sáez-Cirión / Virology 454-455 (2014) 340–352 promoter depends on the recruitment of the HIV transactivator the mammalian target of rapamycin (mTOR), a protein kinase that factor Tat to the transactivation-responsive element (TAR) located at control cell cycle, proliferation and survival, and plays a critical the end of initial HIV transcripts ).
role in the differentiation of T cells. Rapamycin has been shown to Compounds such as Celastrol ) directly block be able to block HIV infection in vitro ) by Tat function by altering its structure. An analogue of Cortistatin A, a decreasing the expression of CCR5, and also interferes with the natural steroidal alkaloid, has shown to block HIV transcription synthesis of HIV transcripts ). Through its capacity initiation and elongation by binding specifically to the TAR-binding to suppress activation and proliferation of T cells, rapamycin has domain of Tat and impairing the interaction of Tat with viral RNAs also the potential to block HIV infection by reducing the number of . This promising molecule showed potent target cells and to dodge the maintenance of viral reservoirs inhibitory capacity in vitro at very low concentrations (nM-pM).
through homeostatic proliferation. Rapamycin is commonly used Zinc-finger domains, small protein domains that can be designed to to avoid organ rejection in kidney transplantation when there are bind specific DNA sequences, can be fused to appropriate effector complications associated with calcineurin inhibitors. Interestingly, domains of transcription factors to specifically regulate the expres- a clinical report on a group of 14 HIV infected patients who sion of targeted genes. Zinc-finger transcription factors targeting received kidney transplantation showed that the patients who different regions of the LTR promoter and carrying the repression switched to rapamycin monotherapy after transplantation were domain of the KOX1 protein were able to repress transcription from able to better control HIV replication than those who kept the LTR in infected cells in vitro ). Overall these calcineurin inhibitors Another recent results suggest that different opportunities exist and may be study, which analyzed a larger group of HIV-infected kidney exploited to specifically repress HIV transcription.
recipients, has shown that those who received rapamycin experi-enced, two years after transplantation, some reduction in thelevels of cell associated DNA when compared to patients receiving other immunosuppresors Another compound with cytostatic activities that has been tried The apparent cure of the Berlin patient after receiving HSCT from in the context of HIV infection is hydroxyurea. Hydroxyurea is an a CCR5Δ32 homozygous donor and the impossibility of applying this inhibitor of ribonucleotide reductase (RNR) a key protocol in a large scale have inspired attempts to generate HIV- enzyme responsible for dNTP synthesis that has been shown to play resistant cells through gene therapy One of an important role in regulating HIV infection ( the most promising gene therapy strategies against HIV infection Hydroxyurea, other than maintaining cells in a quiescent state, aims to disrupt the CCR5 gene by expressing an engineered zinc- reduces the levels of intracellular dNTPs thus inhibiting HIV DNA finger nuclease (ZFN). Evidence that ZFN could inactivate CCR5 in synthesis during reverse transcription. Although the impact of primary human CD4þ T cells and in CD34þ hematopoietic stem hydroxyurea in HIV reservoirs has not been evaluated, hydroxyurea cells limiting HIV replication was first obtained in mouse models was shown to act synergically with the nucleoside analogue dida- The results of a Phase I clinical nosine to reduce HIV viral loads in patients trial showed that HIV-infected patients treated with ZFN CCR5 . Despite its promises, hydroxyurea treatment was modified CD4þ T cells (SB-728-T) have sustained increases in the shown to provoke complications, such as blunted CD4þ T cell CD4þ T cells, mostly TCM and TTM with low PD-1 expression. Viremia recovery and severe toxicity, in HIV infected patients ( was controlled after treatment interruption for some patients, but ). Recent studies suggest that these undesirable cART was resumed by most of them due to dual-tropic infection or effects were due to a too high dose of the drug, and that both the viral load rebound Phase II clinical trials are antiviral and the cytostatic activities of hydroxyurea may contribute currently ongoing to evaluate the efficacy of SB-728-T. In a recent to control HIV when used at lower concentrations ( development of these studies, ZFNs have been designed to be JQ1 is an agonist of the bromodomain protein BRD4, which combined and simultaneously target CCR5 and CXCR4. This approach promotes cell cycle progression (BRD4 is also a resulted in human primary CD4þ T cells that were resistant to R5 positive regulator of P-TEFb that competes with Tat for binding to and X4 viruses in vitro and also in vivo when introduced in this complex at the HIV promoter ). JQ1 humanized mice ). This strategy would tackle dissociates BRD4 from the HIV promoter and allows Tat recruit- the risk of tropism switching.
ment and subsequent HIV elongation In addition, Other strategies consist of transducing CD34þ or CD4þ T cells JQ1 appears also to alter chromatin organization and downregu- with vectors expressing (i) shRNA interfering with CCR5 or other key lates T cell activation genes ).
factors associated with the HIV life cycle including A different strategy has been explored with auranofin, a gold- its promoter ); and (ii) small peptides with capacity based compound that has been evaluated in vivo in SIV infected to inhibit HIV entry into the cells ). Another macaques. This compound was shown in vitro to promote differ- encouraging gene therapy approach directly targets the viral reservoir entiation of CD27 þ memory CD4þ T cells to more terminal short- and is based on the ability of a tailored site-specific recombinase (Tre) lived stages () preceding increased cell death.
to excise HIV provirus from host genome ). Recently, Administration of auranofin to a group of SIVmac251 infected successful expression of Tre-recombinase in human cells was demon- rhesus macaques with viral loads suppressed by cART, induced strated. In addition, an important antiviral effect was observed in indeed a decreased in the frequency of TCM and TTM CD4þ T cells, humanized mice, suggesting that this approach may be valuable for the cells thought to contribute the most to persistent reservoirs future HIV eradication strategies ). Interestingly, auranofin treatment wasaccompanied by a transient decrease of viral reservoirs and adelayed rebound of viremia after interruption of auranofin and Innovative approaches to eliminate HIV reservoirs antiretroviral treatment (In a follow-up study,auranofin treatment in two macaques combined with cART and Several experimental and proof-of-concept studies aim to buthionine sulfoximine, a glutathione-depleting agent that has interfere with cell cycle and survival of HIV infected cells to been proposed to favor selective death of infected cells in vitro facilitate their elimination or avoid their persistence by homeo- favored control of infection at relatively low static proliferation. Rapamycin is an immunosuppresor that blocks levels after treatment interruption ( C.P. Passaes, A. Sáez-Cirión / Virology 454-455 (2014) 340–352 How these interventions may impact (positively or negatively) due to the dual role that IFNα (and immune activation) may play at T cell immune defenses against HIV has not been thoroughly different stages of infection.
addressed, and the translation of current formulations of these Immune activation is a major determinant of HIV pathogenesis, drugs to clinical intervention is unlikely due to toxicity and and increased levels of inflammation markers are associated with possible harmful unspecific effects. However, the proof-of- faster progression to disease and CD4þ T cell loss principle studies described above suggest that targeting T cell ) including in HIV controllers with undetectable viremia ( proliferation and survival deserves further attention in the search ). Therefore, targeting the harmful for an HIV cure.
immune activation appears to be a necessary element in ensuring along-life remission of HIV infection. Some of the molecules target-ing HIV reservoirs described in this review have also immunosup-pressive effects, and their impact is being evaluated. Other Immunotherapies to treat HIV infection molecules such as chloroquine analogues or statins specificallytarget inflammation. So far, studies employing these and other There is a consensus in the scientific community on the need to anti-inflammatory molecules have rendered contrasting results potentiate immune responses in the context of combinatory (). Thus, chloroquine administration has been shown approaches to reach an HIV cure. Such responses would contribute to decrease levels of T cell activation but to either control or eliminate HIV infected cells. A study performed produce faster CD4þ T cell loss when used for longer periods of by the Siliciano group showed that reactivation of latent viruses time (). A better knowledge of the best timing to would not automatically entail the elimination of the infected cells implement interventions aimed at decreasing persistent immune by viral-replication-driven apoptosis (). Efficient activation is warranted.
CD8 þ T cell responses, such as those found in HIV controllers,react to very small amounts of antigens and eliminate HIVproducing cells ( Concluding remarks In contrast, responses from non-controllerpatients would not have such capacity. Anti-exhaustion strategies Achieving HIV cure at a global scale through the eradication of try to reverse negative signaling provided by immunoregulatory HIV reservoirs seems still far off. In contrast, durable HIV remission molecules such as PD-1 to restore T cell function, in particular, with low levels of infected cells being controlled by host mechan- the capacity to kill infected cells ().
isms seems more plausible at medium-term horizon. The first step Blockage of PD-1 interactions with PD-1 ligands on SIV-infected in such strategy would be to limit the size of the viral reservoirs.
macaques resulted in the expansion of CD8 þ T cells with Early treatment initiation has been shown to provide immunolo- improved functionality, longer survival, lower viral loads and gical and virological benefits to HIV infected patients, and early delayed viral rebound after antiretroviral treatment interruption treated patients may be more prone to positively respond to cure ). However, another report suggests that mere therapies. Moreover, treatment is prevention () expansion of polyfunctional CD8 þ T cell responses through PD-1 and, thus, early diagnosis and treatment initiation appears as a blockade may not suffice to sustainably decrease viremia priority in the global fight against HIV. Approaches trying to purge A key aspect may be the association of the viral reservoirs, including activation with HDAC inhibitors or the efficient responses found in HIV controllers with the selection PKC agonists face the difficulty of trying to circumvent complex of particular TCR clonotypes in these cells. In this sense, PD-1 mechanisms of repression with non-specific drugs that may cause blockade may be a useful adjuvant in vaccination protocols undesirable effects. An alternative strategy may be to further ) helping to induce efficient responses. This reinforce latency and repression mechanisms with specific mole- review will not summarize therapeutic vaccine strategies cur- cules targeting Tat-dependent transcription of HIV products. Gene rently in development. However, recent results showing that (i) therapy offers also the possibility to target specific genes to render non-conventional CD8 þ T cell responses were associated with cells resistant to HIV infection and even to excise integrated control of infection and viral clearance in a group of macaques provirus. Enhancing susceptibility to apoptosis of HIV infected vaccinated with a cytomegalovirus vector cells or impairing homoeostatic proliferation and persistence of ) despite profound viral dissemination during these cells are also proposed as potential strategies to tackle HIV primary infection; and that (ii) passive transfer of broadly neu- reservoirs. However, such approaches need to carefully evaluate tralising antibodies allows control of infection in chronically SIV- the impact they may have in immune responses of treated infected macaques ), suggest that therapeutic individuals. HIV remission will require efficient host responses to vaccines should be an important element in the global plan to control infected cells and to prevent harmful HIV-related inflam- achieve HIV cure or remission.
mation. These areas of research need to be explore in parallel to So far, interventions based on the administration of gamma- strategies targeting the reservoirs.
chain cytokines such as IL-2, IL-7 or IL-15, which tried to improve Tcell function and restore T cell homeostasis ),have not shown, at least by themselves, significant benefits in HIVtreatment. Indeed, improved immune reconstitution with IL-7 is Our work receives financial support from the ANRS, Sidaction, also accompanied by a significant increase in the total number of amfAR and Total Foundation. C.P.B.P. has postdoctoral funding HIV-harbouring CD4 þ T cells from the ANRS.
). It is not excluded, however, that these cytokines mayhave an important adjuvant effect in vaccine strategies. Therapies based on IFNα administration have been shown to decreaseviremia during chronic infection and reduce viral reservoirs after treatment interruption ( However, these effects were not observed in all situations (which may be C.P. Passaes, A. Sáez-Cirión / Virology 454-455 (2014) 340–352 Ananworanich J., Vandergeeten C., Chomchey N., Chomont N., Early ART interven- tion restricts the seeding of the HIV reservoir in long-lived central memory CD4 T cells., 20th Conference on Retroviruses and Opportunistic Infections, 2013, Atlanta, GA, USA.
Ando D., Lalezari J., Blick G., Rodriquez, J., Hsu R., Hawkins T., Parks D., Zeidan J., Sekaly R-P., Deeks S., Functional Control of Viremia in CCR5-Δ32 Heterozygous (Δ32HZ) HIV+ Subjects Following Adoptive Transfer of Zinc Finger Nuclease CCR5 Modified Autologous CD4 T-cells (SB-728-T). 53rd Interscience Confer- ence on Antimicrobial Agents and Chemotherapy, 2013, Denver, CO, USA.
C.P. Passaes, A. Sáez-Cirión / Virology 454-455 (2014) 340–352 Elliott J., Solomon A., Wightman F., Smith M., Palmer S., Prince M., Watson J., Hoy J., McMahon J, Lewin S.R., The safety and effect of multiple doses of Vorinostat on HIV transcription in HIV-infected patients receiving combination antiretroviral therapy., 20th Conference on Retroviruses and Opportunistic Infections, 2013, Atlanta, GA, USA.
C.P. Passaes, A. Sáez-Cirión / Virology 454-455 (2014) 340–352 Mbonye, U., Karn, J., Transcriptional control of HIV latency: Cellular signaling pathways, epigenetics, happenstance and the hope for a cure. Virology, C.P. Passaes, A. Sáez-Cirión / Virology 454-455 (2014) 340–352 Stock P., Barin B., Hatano H., Rogers R., Roland M., Lee T.-H., Busch M., Deeks S., Impact of immunosuppressive therapies on HIV persistence during kidney transplantation. 2013, 19th International AIDS conference, Kuala Lumpur, C.P. Passaes, A. Sáez-Cirión / Virology 454-455 (2014) 340–352

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