Research toward a cure and immune-based and gene therapies

19 July 2014. Related: Pipeline report, Cure-related research.

By Richard Jefferys

Introduction

Research working toward the goal of curing HIV infection has rapidly assumed a central, prioritized role within the overall scientific portfolio. Funding has not swelled at the same pace, but there have been signs of change over the past year: in December 2013, President Obama announced an additional $100 million in U.S. government support though the National Institutes of Health (NIH), reassigned from areas now considered redundant. [1] In February 2014 the independent funder amfAR launched the “Countdown to a Cure for HIV/AIDS” campaign, which aims to bolster its cure research program to the tune of US$100 million over six years. [2] The International AIDS Society’s “Towards a Cure” initiative is tracking support for cure research in collaboration with AVAC and the HIV Vaccines and Microbicides Resource Tracking Working Group, reporting US$78.2 million in global investments in 2012 [3] (the 2013 figures will be released in July 2014).

The number of clinical trials under way has increased substantially since 2013, as has the diversity of approaches being evaluated (see table 1). However, with two notable exceptions, there is no expectation that this early generation of studies will lead to cures; rather, the hope is that information can be generated that will help achieve that goal in the future. One exception comprises the attempts to repeat the outcome achieved in Timothy Ray Brown, the lone adult considered cured of HIV, in other HIV-positive people who have cancers requiring treatment with stem cell transplants. Two trials, one for adults and another for younger individuals (BMT CTN 0903 and IMPAACT P1107), will attempt to locate appropriate stem cell donors heterozygous for the CCR5-Δ32 mutation, as was done in Brown’s case. This approach is suitable only for people with life-threatening cancers, due to the high mortality rate associated with stem cell transplantation. The dangers of the procedure were highlighted last year when a 12-year-old boy with HIV and cancer received cord blood stem cells heterozygous for the CCR5-Δ32 mutation, with the aim of curing both diseases, but died shortly afterward due to graft-versus-host disease (a condition that can occur if the transplanted cells are recognized as foreign and attacked by the immune system). [4]

The second instance where there may be reason for optimism about the possibility of achieving cures is a clinical trial based on the case of the “Mississippi baby.” This case was first publicly reported at the Conference on Retroviruses and Opportunistic Infections (CROI) in March of 2013 and subsequently published in the New England Journal of Medicine last October. [5] An update at CROI 2014 revealed that the child is now over three years old and remains in remission, possibly cured, with no HIV activity detectable after nearly two years off antiretroviral therapy (ART). [6] The salutary outcome is believed to be a result of receiving approximately 18 months of ART that was started immediately after birth. The trial, IMPAACT P1115, to be conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT), involves immediate treatment of babies infected with HIV because their mothers failed to receive appropriate prevention of mother-to-child transmission (PMTCT). While the possibility of sparing these newborns a lifelong burden of ART needs to be pursued, the goal of ensuring that no HIV-positive mother lacks access to PMTCT remains paramount.

The remaining cure research pipeline consists largely of early-phase studies, such as those testing agents that might have the potential to coax the latent HIV reservoir out of hiding. Strategies such as therapeutic vaccination and gene therapy, which were previously considered separately in this chapter of the Pipeline Report, are now included under the cure umbrella as they are generally viewed as part of the field. Definitions in this realm can be somewhat fuzzy, however, and some candidates may end up also being assessed to see if they can add benefit to ongoing ART.

As noted in previous Pipeline Reports, the number of candidate immune-based therapies being evaluated specifically for use as an adjunct to ART has dwindled. But there remains a potential need: a recent analysis of a large cohort of HIV-positive people receiving ART in Europe reported that 15 percent (835 out of 5,550), of those starting with low CD4 T-cell counts failed to surpass the threshold of 200 cells/mm3 despite more than three years of HIV viral-load suppression. [7] These individuals faced a significantly increased risk of illness and death. Furthermore, elevated inflammation and immunologic perturbations characteristic of old age, particularly a low CD4/CD8 ratio, can persist among individuals on long-term ART and remain targets for immune-based interventions due to associations with non-AIDS-defining illnesses and mortality. [8, 9]

Note: Some candidates likely to be the subject of further research are included, although they are not currently in an ongoing trial (entries where the trial is noted as completed). For a more extensive listing of completed trials related to cure research, with links to published and presented results where available, see
http://www.treatmentactiongroup.org/cure/trials.

Stem Cell Transplants

Among the most significant news over the past year was an update on two HIV-positive individuals from the Boston area, who had shown indications of having been cured after receiving stem cell transplants to treat cancers. Unlike Timothy Brown, these individuals received transplants from donors wild-type for the CCR5-Δ32 mutation, meaning the cells expressed normal levels of the HIV coreceptor CCR5. An initial published paper describing the cases indicated that HIV reservoirs were significantly depleted, possibly even eradicated, but at that time ART was still being maintained. [10] In July 2013, the first data was reported from the period after both individuals interrupted ART, and the news appeared good; HIV remained undetectable. [11] But another update in December brought bad tidings: HIV replication had rebounded, after 12 weeks in one case and 32 weeks in the other. [12] Timothy Henrich presented details at CROI 2014, showing that viral load reached very high levels in both individuals, but was ultimately successfully re-suppressed by ART. Genetic sequencing confirmed that the source of the recrudescence in viral replication was the same HIV present prior to the stem cell transplants, and not a new infection. [13] The outcome is obviously disappointing, but also contributes important information to the cure research effort. Among the implications:

• Timothy Brown’s receipt of a stem cell transplant from a donor heterozygous for the CCR5-Δ32 mutation may have been crucial to the cure achieved in his case (Brown continues to show no signs of HIV activity off ART).
• The significant diminution in the size of the latent HIV reservoir in the Boston patients (greater than three logs) was insufficient to result in a permanent cure, suggesting that the bar is set very high for approaches that aim to cure HIV infection by reducing the number of latently infected cells. This finding appears to be consistent with a mathematical model developed by Alison Hill and colleagues, which suggests that reservoir reductions of greater than five or six logs (100,000-fold or a million-fold) may be needed to cure the majority of patients. [14]
• Long-term monitoring of HIV viral load is essential in any case where it is suspected that a cure might have occurred, because late viral rebound is possible.
• The inability to detect HIV using the most sensitive current assays does not necessarily mean that no virus is present in the body.

In an attempt to circumvent the difficulty of identifying stem cell donors heterozygous for the CCR5-Δ32 mutation for people with HIV and cancers requiring transplants (as was done for Timothy Brown), several trials are testing whether stem cells can be genetically modified to create resistance to HIV. Earlier this year, the City of Hope National Medical Center in California opened enrollment for a study for HIV-positive people with non-Hodgkin’s lymphoma that will modify stem cells with three different RNA-based HIV inhibitors, and administer the chemotherapy drug busulfan in an attempt to promote the engraftment of the gene-modified cells. The Fred Hutchinson Cancer Research Center has a trial pending that plans to alter stem cells with a gene encoding an HIV entry inhibitor, C46; it will be open to individuals with either non-Hodgkin’s or Hodgkin’s lymphoma.

Updates on SB-728-T

Sangamo BioSciences is attempting to turn the lessons from the Timothy Brown case into a more accessible gene therapy approach for HIV. Rather than involving stem cell transplants, SB-728-T aims to disable CCR5 genes in CD4 T cells extracted from HIV-positive individuals; the cells are then expanded and reinfused. The goal is to create a population of CD4 T cells that are resistant to HIV because they do not express the CCR5 coreceptor. Results from one of the first phase I trials of SB-728-T received high-profile publication in the New England Journal of Medicine in March 2014. [15] In the 12 HIV-positive participants, the treatment was safe, with transient infusion reactions the main side effect. CD4 T-cell counts were increased significantly, and gene-modified CD4 T cells persisted at low levels (~1–2% of circulating CD4 T cells) during long-term follow-up. Six participants underwent a 12-week ART interruption, and an intriguing finding was that one of these individuals experienced a viral-load rebound followed by a decline to undetectable levels just before ART was reinitiated (three of the other participants showed viral-load set points similar to those pre-ART, while the remaining two had to restart ART quickly due to high viral loads).

Further analysis revealed that this last individual is heterozygous for the CCR5-Δ32 mutation, meaning that one copy of the CCR5 gene is already disabled in the person’s CD4 T cells (each cell contains two CCR5 genes, one on each set of chromosomes). As a result, there was less work for SB-728-T to do: it had to disable only one CCR5 gene in each CD4 T cell in order to completely abrogate expression of the CCR5 receptor. The lesson Sangamo BioSciences has drawn from this fortuitous case is that maximizing the number of CD4 T cells modified to lack CCR5 may be able to lead to control of HIV in the absence of ART. The possibility is being explored further in two ongoing trials; one has recruited only CCR5-Δ32 heterozygotes, and the other is administering a chemotherapy drug, cyclophosphamide (Cytoxan), prior to the CD4 T-cell infusions. The rationale for the latter strategy is that Cytoxan should reduce the number of existing CD4 T cells, and thus create more immunologic space for the gene-modified cells to expand into.

At CROI 2014, Gary Blick presented some preliminary data from the trial involving Cytoxan. [16] The uptake of gene-modified cells appeared to be enhanced in the two recipients of the highest Cytoxan dose, and these individuals also experienced significant viral declines during an ART interruption, but it is not possible to draw conclusions based on the small number of participants involved. An additional cohort is now being recruited that will receive a slightly higher Cytoxan dose. Blick noted that there is an inverse correlation between the number of gene-modified CD4 T cells and viral-load levels during ART interruptions, suggesting better results are attainable if the numbers can be further boosted. Blick also highlighted that one participant in the trial for CCR5-Δ32 heterozygotes has maintained a viral load of less than 50 copies/mL for an extended period after ART interruption (31 weeks at the time of the report).

Latency-Reversing Agents

HDAC inhibitors, a class of anticancer drugs, continue to represent lead candidates for rousting latent HIV from dormancy. Results from a phase I trial of panobinostat in people on ART suggest the drug was successful in prompting at least some latently HIV-infected cells to begin making HIV RNA, [17] a possible first step toward targeting these cells for elimination. Similar findings have previously been reported from two phase I evaluations of the HDAC inhibitor vorinostat. [18, 19] However, recent studies have raised questions about the effectiveness of HDAC inhibitors and other proposed latency-reversing agents (LRAs). The problem is that inducing latent HIV to generate viral RNA may not necessarily be sufficient to lead to the generation of viral proteins and the production of new viruses. Triggering these latter steps in the HIV life cycle is believed to be necessary in order for the latently infected cell to be destroyed, either by the immune system or viral cytopathic effects.

The laboratory of Robert Siliciano at the Johns Hopkins University tested the activity of several LRAs, including the HDAC inhibitors panobinostat, vorinostat, and romidepsin, using latently infected CD4 T cells isolated from HIV-positive individuals on ART. None of the LRAs significantly increased HIV production. [20] However, preliminary follow-up experiments presented at CROI 2014 offered hints that combinations of LRAs may perform better. [21] Additionally, an assessment of romidepsin by another laboratory has reported seemingly contradictory evidence that the drug induced latent HIV to produce new viruses. [22] It is hoped that greater clarity about the potential of HDAC inhibitors will be provided by two trials of romidepsin in people on ART that began this year—one being conducted by the AIDS Clinical Trials Group (ACTG) in the United States, the other by researchers at Aarhus University in Denmark.

The latter study is divided into two parts, A and B. Part A administers romidepsin, while part B combines romidepsin with the therapeutic vaccine Vacc-4x. The goal is to assess whether the combination can deliver a one-two punch to the HIV reservoir, with the vaccine intended to enhance the ability of the immune system to target and eliminate any latently infected cells that are induced to produce viruses by romidepsin. Vacc-4x consists of selected peptides from conserved regions of the HIV p24 protein, and has been associated with lower viral-load rebounds after ART interruption in a previous phase II clinical trial. [23]

Among the other news regarding LRAs was publication of the results of the first trial of the anti-alcoholism drug disulfiram.[24] Although not clear-cut, there was some indication of a stimulating effect on latent HIV occurring shortly after disulfiram administration, and this observation is now being followed up in another, larger study. Interest in toll-like receptor (TLR) agonists as possible LRAs was highlighted in TAG’s 2013 Pipeline Report, and Rockefeller University has since launched a trial of poly-ICLC, a TLR-3 agonist more commonly used as a vaccine adjuvant, in order to assess its effect on the latent HIV reservoir.

Targeting PD-1

PD-1 is a signaling molecule that can be expressed on the surface of CD4 T cells. Transient expression of PD-1 is associated with T-cell activation, while the persistent presence of the molecule is linked to a type of cellular dysfunction referred to as T-cell exhaustion. PD-1 delivers signals to the cell by interacting with molecules expressed by other cells, specifically the PD-1 ligands PD-L1 and PD-L2. PD-1 has emerged as a target in cure research for two reasons: because it is preferentially expressed by latently infected CD4 T cells, [25] and because antibodies against PD-1 may be able to restore the functions of HIV-specific CD4 and CD8 T cells that have become exhausted. [26]

In collaboration with Bristol-Myers Squibb, the ACTG has now launched the first clinical trial in HIV of an antibody that targets PD-1 signaling by blocking PD-L1. Encouraging results from preclinical experiments in SIV-infected macaques were presented at CROI 2014, indicating that the antibody has the potential to beneficially modulate viral replication. [27] However, safety will need to be carefully assessed, as the PD-1 pathway is also involved in the prevention of autoimmunity. [28]

The ACTG had also been planning to conduct a clinical trial of an antibody against PD-1 developed by Merck, but disappointingly the company recently withdrew support. The reasons for the decision are unknown, but may be due to Merck’s seeking FDA approval of the antibody for the treatment of cancer (a condition for which it has shown great promise [29]).

Broadly Neutralizing Antibodies

The research effort to identify and characterize broadly neutralizing antibodies (bNAbs) has been driven primarily by the desire to develop an effective preventive HIV vaccine (see “Preventive Technologies,” p. 55). But the past year has seen a surge in interest in exploring the therapeutic potential of bNAbs due to promising results reported in both HIV-infected humanized mice [30] and SIV-infected macaques. [31, 32] In particular, an experiment performed by the laboratory of Dan Barouch showed that, in some macaques with low-baseline SIV viral loads, short-term administration of a bNAb was associated with sustained control of SIV replication after therapy was stopped. Barouch found evidence of enhanced clearance of SIV-infected cells in the treated animals, suggesting that the bNAb had boosted antibody-mediated effector mechanisms capable of promoting the recognition and killing of these cells. [33] Two phase I human trials testing the effects of infusions of bNAbs are now under way.

Therapeutic Vaccines

In addition to the combination study involving Vacc-4x and romidepsin, new trials of therapeutic vaccines include an evaluation of AGS-004 being conducted by investigators associated with the Collaboratory of AIDS Researchers for Eradication (CARE), one of three cure research consortiums funded by the NIH under its Martin Delaney Collaboratory program. AGS-004 is being developed by Argos Therapeutics and represents a personalized approach to vaccination: dendritic cells are extracted from study participants, mixed with HIV antigens derived from the same individual’s infecting virus, and then administered as a vaccine. The goal is to induce potent immune responses capable of targeting the HIV present in the recipient. Prior studies have produced some evidence that immune responses created by the vaccine are associated with a delayed HIV viral-load rebound during ART interruption, [34] but the CARE researchers will be looking at the impact of immunization on the HIV reservoir and residual viral replication in HIV-positive people on continuous ART.

VAC-3S is a novel candidate that induces antibody responses to a specific part of HIV’s gp41 envelope protein: a motif named 3S. The rationale for the development of the vaccine derives from evidence that these antibodies might protect against some of HIV’s pathogenic effects on the immune system, by interfering with a putative mechanism of CD4 T-cell depletion. [35] A phase I/IIa trial demonstrated safety and immunogenicity, [36] and a phase II study has been launched as a result. The vaccine provides an example of the overlap between immune-based therapy and cure research, as the investigators hypothesize that it might reduce both inflammation and the HIV reservoir.

Interleukin-7 (IL-7)

Unfortunately, the fate of IL-7 illustrates the challenges associated with developing adjunctive immune-based therapies for people with poor immune reconstitution despite ART (immunologic nonresponders, or INRs). IL-7 has been shown to significantly increase CD4 T-cell counts, [37] and a recent small study uncovered evidence that it also diminishes levels of important inflammatory biomarkers. [38] The manufacturer, Cytheris, had ambitious plans to conduct a phase III clinical endpoint trial in INRs, but earlier this year the news emerged that the company had gone out of business. The rights for pursuing IL-7 as a therapy for HIV-related immune impairment have reportedly been taken over by a collaboration involving the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) and Cognate Biosciences. At best, this will certainly delay evaluation of the ability of IL-7 to reduce morbidity and mortality in INRs. At this time, it appears to be the only candidate with sufficient data to justify such a trial, so INRs are likely to be left without therapeutic options beyond ART for some time.

Targeting the Gut to Reduce Immune Activation

Four recent trials analyzed whether treatments that target the gut might diminish immune activation and inflammation in HIV infection. The rationale is that reduction of microbial translocation—the leakage of normally friendly bacteria from the gut into the systemic circulation—should lessen stimulation of the immune system. While not necessarily immune-based, these approaches aim to work via an immunologic mechanism. However, they had little or no effect. Sevelamer is a treatment for reducing high blood levels of phosphorus in kidney disease that can also bind to bacterial endotoxin (lipopolysaccharide), a product of microbial translocation. An eight-week trial in HIV-positive people who had not yet started ART did not uncover any significant effects on markers of microbial translocation or inflammation, although there were significant reductions in LDL cholesterol and tissue factor, suggesting a possible beneficial impact on cardiovascular disease risk. [39] Concerns about potential interactions and overlapping toxicities with ART suggest it is unlikely that sevelamer will have a role as an adjunctive therapy.

Mesalamine is an FDA-approved, bowel-specific anti-inflammatory drug. In a study in HIV-positive people on ART, no changes in either systemic or gut immune activation levels were noted, and inflammatory biomarkers were also unaffected. [40] The antibiotic rifaximin was tested in INRs, but resulted in minimal changes in markers of immune activation and inflammation that did not lead to increases in CD4 T-cell counts. [41]

Some signs of success were seen with a probiotic supplement, Biola, administered to HIV-positive people on ART. Over eight weeks there was a significant decline in levels of D-dimer, an inflammatory biomarker associated with morbidity and mortality in HIV. IL-6 and CRP also fell, but to a less significant extent. [42] A new trial of a probiotic, Saccharomyces boulardii, is taking place in Barcelona, Spain (see table 2).

Panoply of Anti-Inflammatories

A variety of potential anti-inflammatory agents have entered clinical trials over the past year. With the exception of Saccharomyces boulardii, they all aim to work systemically rather than targeting the gut. Among them are sitagliptin, a diabetes drug that has been reported to reduce markers of inflammation in people who are HIV-negative; [43] low-dose methotrexate, an immune suppressant; losartan, an anti-hypertensive; and dipyridamole, indicated for the prevention of blood clots. The vitamin niacin is also being evaluated in a trial in Canada that will look at both immune activation and inflammatory biomarkers.

Conclusion

The opening of new trials and influx of additional funding—albeit still insufficient for the task at hand—demonstrate that momentum is continuing to build in HIV cure research. Although another year has passed without additional proven cases mirroring those of Timothy Brown and the “Mississippi baby” (now a child), there is hope that this situation may change in the not-too-distant future. But the development of widely accessible interventions capable of curing the majority of HIV-positive people remains a stern challenge with no solution imminent. For this reason, the bulk of the cure research that has entered the clinic represents tentative exploratory steps aiming to inform the next round of trials. Advocacy continues to be essential for spurring these efforts, ensuring that funding support grows, and enhancing understanding of the science among the HIV/AIDS community and broader public.

The immune-based therapy field, in contrast, lies disconcertingly fallow. Small studies of anti-inflammatory approaches are still opening, but it is difficult to envision any leading to licensure of adjunctive treatments capable of reducing the residual risk of morbidity and mortality that can persist among ART recipients, particularly INRs. Commercial interest in this area seems meager. A broader dialogue among activists, scientists, funders, pharmaceutical companies, and other interested parties may be needed in order to assess whether the problems in this area can be solved.

Endnotes

1. National Institutes of Health. NIH announces plan to increase funding toward a cure for HIV/AIDS. 2013 December 2. Available from:
   http://www.nih.gov/news/health/dec2013/niaid-02.htm. (Accessed 2014 April 24)
2. AmfAR (Press Release). AmfAR Launches initiative aimed at finding a cure for HIV by 2020. 2014 February 3. Available from:
   http://www.amfar.org/amfar-launches-initiative-aimed-at-finding-a-cure-for-hiv-by-2020/. (Accessed 2014 April 24)
3. IAS HIV Cure Resource Tracking Group and the HIV Vaccines and Microbicides Resource Tracking Working Group. Global investment in HIV cure research and development in 2012. 2014 July. Available from:
   http://www.iasociety.org/Web/WebContent/File/HIV_Cure_Resource_Tracking_Paper_2012.pdf. (Accessed 2014 April 24)
4. University of Minnesota Academic Medical Center Health Talk. Pediatric patient dies after undergoing historic transplant at U of M. 2013 July 13. Available from:
   http://www.health.umn.edu/healthtalk/2013/07/13/pediatric-patient-dies-after-undergoing-historic-transplant-at-u-of-m/. (Accessed 2014 April 24)
5. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med. 2013 Nov 7;369(19):1828–35. doi: 10.1056/NEJMoa1302976. Epub 2013 Oct 23.
6. Persaud D, Deveikis A, Gay H, et al. Very early combination antiretroviral therapy in perinatal HIV infection: two case studies (Abstract 75LB). Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections; 2014 March 3–6; Boston, MA.
7. Engsig FN, Zangerle R, Katsarou O, et al. Long-term mortality in HIV-positive individuals virally suppressed for >3 years with incomplete CD4 recovery. Clin Infect Dis. 2014 May;58(9):1312–21. doi: 10.1093/cid/ciu038.
8. Lederman MM, Funderburg NT, Sekaly RP, Klatt NR, Hunt PW. Residual immune dysregulation syndrome in treated HIV infection. Adv Immunol. 2013;119:51–83. doi: 10.1016/B978-0-12-407707-2.00002-3.
9. Serrano-Villar S, Sainz T, Lee SA, et al. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog. 2014 May 15;10(5):e1004078. doi: 10.1371/journal.ppat.1004078.
10. Henrich TJ, Hu Z, Li JZ, et al. Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. J Infect Dis. 2013 Jun 1;207(11):1694–702. doi: 10.1093/infdis/jit086.
11. Henrich T, Hanhauser E, Sirignano M, et al. In depth investigation of peripheral and gut HIV-1 reservoirs, HIV-specific cellular immunity, and host microchimerism following allogeneic hematopoetic stem cell transplantation (Abstract WELBA05). Paper presented at: 7th International AIDS Society Conference. June 30–July 3, 2013; Kuala Lumpur, Malaysia.
12. Partners AIDS Research. Statement from Dr. Timothy Henrich regarding HIV patients. 2013 December 6. Available from:
    http://www.scribd.com/doc/189931630/12-06-13-Statement-From-Dr-Henrich-Regarding-HIV-Patients. (Accessed 2014 May 1)
13. Henrich TJ, Hanhauser E, Sirignano MN, et al. HIV-1 rebound following allogeneic stem cell transplantation and treatment interruption (Abstract 144LB). Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections; 2014 March 3–6; Boston, MA.
14. Hill A, Rosenbloom D, Nowak M, Siliciano R. Predicting outcomes of treatments to eradicate the HIV latent reservoir (Abstract 386). Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections; 2013 March 3–6; Atlanta, GA.
15. Tebas P, Stein D, Tang WW, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014 Mar 6;370(10):901–10. doi: 10.1056/NEJMoa1300662.
16. Blick G, Lalezari J, Hsu R, et al. Cyclophosphamide enhances SB-728-T engraftment to levels associated with HIV-RNA control (Abstract 141). Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections; 2014 March 3–6; Boston, MA.
17. Rasmussen T, and the CLEAR study group. Panobinostat induces HIV transcription and plasma viremia in HIV patients on suppressive cART (Abstract 438LB). Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections; 2014 March 3–6; Boston, MA.
18. Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012 Jul 25;487(7408):482–5. doi: 10.1038/nature11286. Erratum in: Nature. 2012 Sep 20;489(7416):460.
19. Elliott J, Solomon A, Wightman F, et al. The safety and effect of multiple doses of vorinostat on HIV transcription in HIV+ patients receiving cART (Abstract 50LB). Paper presented at: 20th Conference on Retroviruses and Opportunistic Infections; 2013 March 3–6; Atlanta, GA.
20. Bullen CK, Laird GM, Durand CM, Siliciano JD, Siliciano RF. New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med. 2014 Apr;20(4):425–9. doi: 10.1038/nm.3489. Epub 2014 Mar 23.
21. Laird GM, Bullen CK, Siliciano JD, Siliciano RF. Novel ex vivo approaches distinguish effective and ineffective drugs for reversing latency in vivo (Abstract 139). Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections; 2014 March 3–6; Boston, MA.
22. Wei DG, Chiang V, Fyne E, et al. Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing. PLoS Pathog. 2014 Apr 10;10(4):e1004071. doi: 10.1371/journal.ppat.1004071.
23. Pollard RB, Rockstroh JK, Pantaleo G, et al. Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2014 Apr;14(4):291–300. doi: 10.1016/S1473-3099(13)70343-8.
24. Spivak AM, Andrade A, Eisele E, et al. A pilot study assessing the safety and latency-reversing activity of disulfiram in HIV-1-infected adults on antiretroviral therapy. Clin Infect Dis. 2014 Mar;58(6):883–90. doi: 10.1093/cid/cit813.
25. Chomont N, El-Far M, Ancuta P, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009 Aug;15(8):893–900. doi: 10.1038/nm.1972.
26. Porichis F, Kaufmann DE. Role of PD-1 in HIV pathogenesis and as target for therapy. Curr HIV/AIDS Rep. 2012 Mar;9(1):81–90. doi: 10.1007/s11904-011-0106-4.
27. Mason SW, Sanisetty S, Osuna-Gutierrez C, et al. Viral suppression was induced by Anti-PD-L1 following ARV-interruption in SIV-infected monkeys (Abstract 318LB). Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections; 2014 March 3–6; Boston, MA.
28. Gianchecchi E, Delfino DV, Fierabracci A. Recent insights into the role of the PD-1/PD-L1 pathway in immunological tolerance and autoimmunity. Autoimmun Rev. 2013 Sep;12(11):1091–100. doi: 10.1016/j.autrev.2013.05.003.
29. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134–44. doi: 10.1056/NEJMoa1305133.
30. Horwitz JA, Halper-Stromberg A, Mouquet H, et al. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16538–43. doi: 10.1073/pnas.1315295110.
31. Shingai M, Nishimura Y, Klein F, et al. Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature. 2013 Nov 14;503(7475):277–80. doi: 10.1038/nature12746.
32. Barouch DH, Whitney JB, Moldt B, et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature. 2013 Nov 14;503(7475):224–8. doi: 10.1038/nature12744.
33. Picker LJ, Deeks SG. HIV: Antibodies advance the search for a cure. Nature. 2013 Nov 14;503(7475):207–8. doi: 10.1038/nature12703.
34. DeBenedette M, Tcherepanova I, Gamble A, Horatinovich J, Harris J, Routy J-P, Nicolette C, AGS-004-001 Study Team. Immune function and viral load post AGS-004 administration to chronic HIV subjects undergoing STI (Abstract 343). Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections; 2014 March 3–6; Boston, MA.
35. Petitdemange C, Achour A, Dispinseri S, et al. A single amino-acid change in a highly conserved motif of gp41 elicits HIV-1 neutralization and protects against CD4 depletion. Clin Infect Dis. 2013 Sep;57(5):745–55. doi: 10.1093/cid/cit335.
36. Katlama C, Launay O, Gharakhanian S, et al. Evidence and potential immunotherapeutic applications of vaccine-induced antibodies against 3S, a highly conserved motif of gp41, in HIV-1-infected patients treated with antiretroviral therapy (Abstract 145). Paper presented at: 30 Years of HIV Science conference; 2013 May 21–23; Paris, France.
37. Lévy Y, Sereti I, Tambussi G, et al. Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study. Clin Infect Dis. 2012 Jul;55(2):291–300. doi: 10.1093/cid/cis383.
38. Sereti I, Estes JD, Thompson WL, et al. Decreases in colonic and systemic inflammation in chronic HIV infection after IL-7 administration. PLoS Pathog. 2014 Jan 30;10(1):e1003890. doi: 10.1371/journal.ppat.1003890.
39. Sandler NG, Zhang X, Bosch RJ, et al. Sevelamer does not decrease lipopolysaccharide or soluble CD14 but does decrease soluble tissue factor, LDL, and oxidized LDL levels in untreated HIV infection. J Infect Dis. 2014 May 26. pii: jiu305. [Epub ahead of print].
40. Somsouk M, Dunham RM, Cohen M, et al. Mesalamine to reduce immune activation during HIV infection: a randomized controlled trial (Abstract 341). Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections; 2014 March 3–6; Boston, MA.
41. Tenorio AR,. Wilson CC, Chan ES, et al. Rifaximin has marginal impact on immune activation in immune non-responders to ART – ACTG 5286 (Abstract 339). Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections; 2014 March 3–6; Boston, MA.
42. Stiksrud B, Nowak P, Kvale D, et al. Decreased levels of D-dimer after probiotic supplementation in patients receiving ART (Abstract 342). Paper presented at: 21st Conference on Retroviruses and Opportunistic Infections; 2014 March 3–6; Boston, MA.
43. Makdissi A, Ghanim H, Vora M, et al. Sitagliptin exerts an antinflammatory action. J Clin Endocrinol Metab. 2012 Sep;97(9):3333–41. doi: 10.1210/jc.2012-1544.