Research Toward a Cure and Immune-Based and Gene Therapies
The rise to prominence of cure research has continued over the past year, with every major scientific conference on HIV now featuring sessions and presentations on the topic. The U.S. National Institute of Allergy and Infectious Diseases (NIAID) sponsors a biannual workshop with the most recent, Strategies for an HIV Cure, taking place in Bethesda in October 2014. The NIAID meeting alternates years with another more longstanding event known as the International HIV Persistence Workshop, which debuted in 2003 and will convene for the seventh time in December 2015. In addition, the International AIDS Society (IAS) sponsors a two-day symposium, Towards an HIV Cure, every year in July.
The proliferation of meetings and workshops reflects the expansion of the research effort and the resultant data, which are presented and discussed at these events. Since the publication of the 2014 Pipeline Report, many new clinical trials have been initiated (see table 1), and important results from early human studies of candidate HIV latency-reversing agents have been presented and published.
The most significant development has been a disappointment: the child once known as the Mississippi baby, considered possibly cured of HIV infection, experienced a viral-load rebound and had to restart antiretroviral therapy (ART). The news was announced July 10, 2014,  and a case report published in the New England Journal of Medicine in February of this year.  ART had been initiated shortly after the child’s birth and then interrupted around 18 months later; the child subsequently went 27 months with no detectable viral load or replication-competent HIV before the rebound occurred. An International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network trial based on the case, P1115, has gone ahead and will attempt to evaluate whether similar or longer periods of remission can be obtained by immediate treatment of newborns infected with HIV because their mothers did not receive appropriate prevention of mother-to-child transmission.
With the return of HIV in the Mississippi child, Timothy Brown once again became the lone individual considered cured (he recently celebrated reaching eight years with this unique status). Gero Hütter, the doctor who identified a stem cell donor homozygous for the CCR5-Δ32 mutation for Brown and performed the transplantation procedures, recently reviewed six other documented cases of people with HIV and cancers who received stem cell transplants from CCR5-Δ32 homozygotes. In a stark and unhappy illustration of the challenges associated with the approach, all six died within a few months, due to either the underlying cancers or complications from the transplantation procedures such as graft-versus-host-disease.  In one case, HIV had become undetectable, but ART was not discontinued to evaluate the potential for viral-load rebound, and the individual died from the cancer three months posttransplant.  The high mortality has raised some concerns, as recent reports indicate a superior survival rate, of 47%, among HIV-positive individuals receiving stem cell transplants from donors lacking the CCR5-Δ32 mutation. [5, 6] Two ongoing trials in the United States continue to attempt to identify CCR5-Δ32 homozygous donors for people with HIV who need stem cell transplants to treat cancers (see table 1), and a similar effort is under way in Europe led by the IrsiCaixa Institute for AIDS Research in Spain. 
Clearly, hopes have significantly diminished that additional cases of cures might result in the near term from immediate ART in infants or CCR5-negative stem cell transplants for people with HIV and cancers. While more cases would have been encouraging for the field, they would not necessarily have aided in the design of more broadly relevant approaches. The majority of current clinical trials represent attempts to create stepping stones toward a cure or the intermediate outcome of extended ART-free remission.
On the funding front, a report from the HIV Vaccines and Microbicides Resource Tracking Working Group (in partnership with AVAC and the Towards an HIV Cure initiative) estimates that global investment in HIV cure research was US$102.7 million in 2013, up from US$88.1 million in 2012  – still a very small proportion of overall spending on HIV research. More recently, amfAR, the Foundation for AIDS Research, announced a further expansion of its cure research program, to the tune of US$100 million over the next several years,  and NIAID has announced a request for funding applications that will lead to the support of three or four Martin Delaney Collaboratories focused on the development of an HIV cure starting in mid-2016 (after the current grants supporting the Collaboratory of AIDS Researchers for Eradication (CARE), Delaney AIDS Research Enterprise, and defeatHIV, the Delaney Cell and Genome Engineering Initiative expire). A little over US$22 million will be allocated in FY 2016, primarily from NIAID with contributions from the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke.  Notably, when the director of the U.S. National Institutes of Health (NIH), Francis Collins, asked the Office of AIDS Research Advisory Council to identify the key priorities for future funding, the pursuit of a cure was ranked prominently among them. 
For the most part, immune-based and gene therapies have become integrated into the cure research effort. There is now relatively little exploration of approaches that might be added to ART in order to reduce the residual risk of illness that can persist in some individuals, particularly those who experience poor recovery of CD4+ T cells despite effective viral-load suppression (referred to as immunologic nonresponders, or INRs). Immunologic nonresponse to ART and more subtle manifestations of persistent immune dysregulation such as elevated levels of inflammatory biomarkers and low CD4:CD8 ratios have been associated with a significantly increased risk of morbidity and mortality. [12, 13] In the absence of immune-based interventions, evidence indicates that the best approach to minimizing risk is to address modifiable lifestyle factors such as smoking, diet, and exercise. Excercise has been reported to have positive immunologic effects including lowering markers of immune senescence. [14, 15]
There is one very large clinical endpoint trial of a possible adjunct to ART that has been launched this year. Known as the REPRIEVE trial, it will assess whether the statin drug pitavastatin can reduce the incidence of cardiovascular disease in people on ART; it aims to recruit 6,500 participants.  In addition to lipid-lowering effects, some statins have been reported to reduce inflammatory and immune activation biomarkers in HIV-positive individuals. [17, 18] Changes in the inflammatory biomarkers RP, Lp-PLA2, and sCD163 will be evaluated in a REPRIEVE substudy. 
|Trial||Additional Description||Trial Registry Identifier(s)*||Manufacturer/Sponsor(s)||Phase|
|Early ART in combination with autologous HIV-specific cytotoxic T-lymphocyte (CTL) infusion||T-cell therapy||NCT02231281||Yong-Tao Sun, Tangdu Hospital, Fourth Military Medical University||Phase III|
|HXTC||HIV-1 antigen-expanded specific T-cell therapy||NCT02208167||University of North Carolina (UNC) at Chapel Hill||Phase I|
|3BNC117||Broadly neutralizing monoclonal antibody||NCT02018510||Rockefeller University||Phase I|
|BMS-936559||Anti-PD-L1 antibody||NCT02028403 (suspended)||U.S. National Institute of Allergy and Infectious Diseases (NIAID)||Phase I|
|VRC01||Broadly neutralizing monoclonal antibody + ART interruption||NCT02463227(not yet open for enrollment)||NIAID||Phase I|
|VRC01||Broadly neutralizing monoclonal antibody||NCT02411539(not yet open for enrollment)||NIAID||Phase I|
|VRC01||Broadly neutralizing monoclonal antibody||NCT01950325||NIAID||Phase I|
|CHERUB 001||Intravenous immunoglobulin in primary HIV infection||No clinicaltrials.gov entry yet||CHERUB (Collaborative HIV Eradication of viral Reservoirs: UK BRC)||N/A|
|ACE inhibitors||NCT01535235||University of California, San Francisco/amfAR||Phase IV|
|losartan||Angiotensin receptor blocker||NCT01852942||University of Minnesota||Phase I|
|Antiretroviral Therapy in HIV Controllers|
|emtricitabine + rilpivirine + tenofovir||NCT01777997 (closed to enrollment)||AIDS Clinical Trials Group (ACTG)/NIAID||Phase IV|
|RIVER (Research In Viral Eradication of HIV Reservoirs): ART + ChAdV63.HIVconsv & MVA.HIVconsv vaccines + vorinostat||Therapeutic vaccines + HDAC inhibitor||NCT02336074(not yet open for enrollment)||Imperial College London||Phase II|
|SB-728mR-T + cyclophosphamide||Autologous CD4+ T cells gene-modified via messenger RNA to inhibit CCR5 expression + transient chemotherapy||NCT02225665||Sangamo BioSciences||Phase I/II|
|SB-728-T + cyclophosphamide||Autologous CD4+ T cells gene-modified via adenovirus vector to inhibit CCR5 expression + transient chemotherapy||NCT01543152||Sangamo BioSciences||Phase I/II|
|Vacc-4x + romidepsin||HDAC inhibitor + peptide-based therapeutic vaccine||NCT02092116||Bionor Immuno AS/Celgene||Phase I/II|
|CD4-ZETA +/- interleukin-2 (IL-2)||Gene-modified T cells + cytokine||NCT01013415(closed to enrollment)||University of Pennsylvania||Phase I|
|SB-728mR-T + cyclophosphamide||Autologous CD4+ T cells gene-modified via messenger RNA to inhibit CCR5 expression + transient chemotherapy||NCT02388594||University of Pennsylvania||Phase I|
|Cal-1: Dual anti-HIV gene transfer construct||Lentiviral vector encoding a short hairpin RNA that inhibits expression of CCR5 + fusion inhibitor (C46)||NCT01734850NCT02390297 (long-term safety phase)||Calimmune||Phase I/II|
|VRX496||Autologous CD4+ T cells modified with an antisense gene targeting the HIV envelope||NCT00295477 (closed to enrollment)||University of Pennsylvania||Phase I/II|
|MazF-T||Autologous CD4+ T cells gene-modified with MazF endoribonuclease gene to inhibit HIV||NCT01787994||Takara Bio/University of Pennsylvania||Phase I|
|Gene Therapies for HIV-positive People With Cancers|
|High-dose chemotherapy with transplantation of gene-modified stem cells for high-risk AIDS-related lymphoma||Stem cells gene-modified to express an HIV entry inhibitor C46||NCT00858793 (suspended)||Universitätsklinikum Hamburg – Eppendorf||Phase I/II|
|HIV-resistant gene-modified stem cells and chemotherapy in treating patients with lymphoma and HIV infection||Stem cells gene-modified to delete CCR5 and express an HIV entry inhibitor C46||NCT02343666||Fred Hutchinson Cancer Research Center||Phase I|
|Gene-modified HIV-protected stem cell transplant in treating patients with HIV-associated lymphoma||Stem cells gene-modified with LVsh5/C46 (Cal-1)||NCT02378922 (not yet open for enrollment)||Fred Hutchinson Cancer Research Center||Phase I|
|Gene therapy and combination chemotherapy in treating patients with AIDS-related non-Hodgkin’s lymphoma||Stem cells gene-modified with a lentivirus vector encoding three forms of anti-HIV RNA (pHIV7-shI-TAR-CCR5RZ)||NCT02337985 (not yet open for enrollment)||City of Hope Medical Center||Not listed|
|Busulfan and gene therapy after frontline chemotherapy in patients with AIDS-related non-Hodgkin’s lymphoma||Stem cells gene-modified with a lentivirus vector encoding three forms of anti-HIV RNA (pHIV7-shI-TAR-CCR5RZ)||NCT01961063||City of Hope Medical Center||Not listed|
|Gene therapy-treated stem cells in patients undergoing stem cell transplant for intermediate-grade or high-grade AIDS-related lymphoma||Stem cells gene-modified with a lentivirus vector encoding three forms of anti-HIV RNA (pHIV7-shI-TAR-CCR5RZ)||NCT00569985||City of Hope Medical Center||Not listed|
|MGN1703||Toll-like receptor 9 (TLR-9) agonist||NCT02443935||University of Aarhus||Phase Ib/IIa|
|poly-ICLC||TLR-3 agonist||NCT02071095||Nina Bhardwaj/ Campbell Foundation/Oncovir||Phase I/II|
|romidepsin||HDAC inhibitor||NCT01933594||ACTG/NIAID/Gilead Sciences||Phase I/II|
|vorinostat||HDAC inhibitor||NCT01319383||UNC at Chapel Hill/NIAID/Merck||Phase I/II|
|ALT-803||Recombinant human superagonist interleukin-15 complex||NCT02191098(not yet open for enrollment)||University of Minnesota – Clinical and Translational Science Institute||Phase I|
|bryostatin-1||PKC agonist||NCT02269605(closed to enrollment)||Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal||Phase I|
|GS-9620||TLR-7 agonist||Not entered in clinicaltrials.gov (closed to enrollment)||Gilead Sciences||Phase I|
|ACTG A5321||Decay of HIV-1 reservoirs in subjects on long-term antiretroviral therapy: the ACTG HIV reservoirs cohort (AHRC) study||Not listed||ACTG||N/A|
|Analytic Treatment Interruption (ATI) to Assess HIV Cure||Antiretroviral treatment interruption||NCT02437526(enrolling by invitation only)||Mayo Clinic||N/A|
|CHERUB 003||Prospective cohort study evaluating the effects of chemotherapy on the HIV reservoir||NCT01902693 (closed to enrollment)||Imperial College London/CHERUB||N/A|
|CODEX (the “Extreme” cohort)||Long-term nonprogressors and HIV controllers||NCT01520844||French National Institute for Health and Medical Research/French National Agency for Research on AIDS and Viral Hepatitis (INSERM/ANRS)||N/A|
|EPIC4||Early Pediatric ART Initiation: Canada Child cure Cohort Study||Not listed||Canadian Institutes of Health Research/Canadian Foundation for AIDS Research/International AIDS Society||N/A|
|Establish and characterize an acute HIV infection cohort in a high-risk population||NCT00796146||Southeast Asia Research Collaboration with Hawaii/Armed Forces Research Institute of Medical Sciences, Thailand/Thai Red Cross AIDS Research Centre||N/A|
|Quantitative measurement and correlates of the latent HIV reservoir in virally suppressed Ugandans||NCT02154035||NIAID||N/A|
|Use of leukapheresis to support HIV pathogenesis studies||NCT01161199||University of California, San Francisco||N/A|
|ULTRASTOP/ERAMUNE-03 (Towards HIV Functional Cure)||Antiretroviral treatment interruption||NCT01876862||Objectif Recherche VACcin Sida/Fondation Bettencourt Schueller||N/A|
|everolimus||Impact of everolimus on HIV persistence following kidney or liver transplant||NCT02429869(not yet open for enrollment)||University of California, San Francisco||Phase IV|
|sirolimus||Safety and efficacy of sirolimus for HIV reservoir reduction in individuals on suppressive ART||NCT02440789(not yet open for enrollment)||ACTG||Phase I/II|
|Stem Cell Transplantation|
|BMT CTN 0903||Allogeneic transplant in individuals with chemotherapy-sensitive hematologic malignancies and coincident HIV infection||NCT01410344||National Heart, Lung, and Blood Institute/National Cancer Institute/Blood and Marrow Transplant Clinical Trials Network||Phase II|
|Immune response after stem cell transplant in HIV-positive patients with hematologic cancer||NCT00968630||Fred Hutchinson Cancer Research Center||Phase II|
|IMPAACT P1107||Cord blood transplantation using CCR5-Δ32 donor cells for the treatment of HIV and underlying disease||NCT02140944||IMPAACT/NIAID/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)||N/A|
|AGS-004||Personalized therapeutic vaccine using patient-derived dendritic cells and HIV antigens||NCT01069809 (closed to enrollment)||Argos Therapeutics||Phase II|
|GTU-MultiHIV + LIPO-5||DNA + lipopeptide vaccines||NCT01492985||INSERM/ANRS||Phase II|
|VAC-3S||Peptide-based vaccine||NCT02041247||InnaVirVax||Phase II|
|VAC-3S||Peptide-based vaccine||NCT02390466(not yet open for enrollment)||InnaVirVax||Phase I/IIa|
|AGS-004||Personalized therapeutic vaccine using patient-derived dendritic cells and HIV antigens||NCT02042248||UNC at Chapel Hill/Argos Therapeutics/U.S. National Institutes of Health||Phase I/II|
|GTU-MultiHIV B clade||DNA vaccine||NCT02457689||Imperial College London||Phase I/II|
|Tat Oyi||Tat protein-based vaccine||NCT01793818 (closed to enrollment)||Biosantech||Phase I/II|
|THV01||Lentiviral vector-based vaccine||NCT02054286||Theravectys S.A.||Phase I/II|
|ChAdV63.HIVcons + MVA.HIVconsv||Chimpanzee adenovirus and modified vaccinia Ankara strain (MVA) viral vector vaccines||NCT01712425 (closed to enrollment)||IrsiCaixa/Fundació Lluita contra la SIDA/Hospital Clinic of Barcelona/ HIVACAT/University of Oxford||Phase I|
|D-GPE DNA + M-GPE MVA||DNA and MVA viral vector vaccines||NCT01881581||Centers for Disease Control and Prevention, China||Phase I|
|HIVAX||Lentiviral vector-based vaccine||NCT01428596||GeneCure Biotechnologies||Phase I|
|iHIVARNA-01||TriMix + HIV antigen naked messenger RNA||NCT02413645(not yet open for enrollment)||Institut d’Investigacions Biomèdiques August Pi i Sunyer||Phase I|
|MAG-pDNA + rVSVIN HIV-1 Gag (DNA + viral vector vaccines)||DNA + vesicular stomatitis virus viral vector vaccines||NCT01859325||NIAID/Profectus Biosciences||Phase I|
|MVA.HIVconsv||Modified MVA viral vector vaccine||NCT01024842 (closed to enrollment)||University of Oxford/Medical Research Council||Phase I|
|Traditional Chinese Medicine|
|Triptolide wilfordii||NCT02219672||Peking Union Medical College||Phase III|
|LEOPARD (Latency and Early Neonatal Provision of Antiretroviral Drugs Clinical Trial)||Combination antiretroviral therapy||NCT02431975(not yet open for enrollment)||Columbia University||Not listed|
|New Era (treatment with multidrug class HAART)||Combination antiretroviral therapy||NCT00908544 (closed to enrollment)||MUC Research||Not listed|
|AAHIV (Antiretroviral therapy for Acute HIV infection)||Combination antiretroviral therapy||NCT00796263||South East Asia Research Collaboration with Hawaii||Phase III|
|EIT (Early Infant HIV Treatment in Botswana)||Combination antiretroviral therapy||NCT02369406||Harvard School of Public Health||Phase II/III|
|peginterferon alfa-2b||NCT02227277||Wistar Institute||Phase II|
|peginterferon alfa-2b||Cytokine||NCT01935089||University of Pennsylvania/ Wistar Institute||Phase II|
|alpha interferon intensification||Cytokine||NCT01295515||NIAID||Phase I/II|
|IMPAACT P1115 (very early intensive treatment of HIV-infected infants to achieve HIV remission)||Combination antiretroviral therapy||NCT02140255||IMPAACT/NIAID/NICHD||Phase I/II|
*For more information about a trial, go to clinicaltrials.gov and enter its trial registry identifier in the search bar.
For a listing including completed trials related to cure research, with links to published and presented results where available, see TAG’s “Research Toward a Cure Trials” web page at:
Concepts of Remission
After the return of viral load in the Mississippi child, some leading researchers – including Nobel laureate Françoise Barré-Sinoussi – are advocating more cautious application of the word cure and the term functional cure (which has never been particularly well defined) and recommending the use of remission instead.  The concept is intended to refer to the ability to safely interrupt ART for some period; however, various different forms of ART-free remission have been described, and precise criteria have yet to be proposed.
The 27-month remission that occurred in the Mississippi case shows similarities with two adults in Boston whose HIV reservoirs were significantly diminished after they received stem cell transplants for the treatment of cancers; both were able to interrupt ART without a return of detectable viral load or replication-competent HIV for periods of 12 and 32 weeks, respectively.  In all three instances, the cause of the remission appears to have been the very small size of the HIV reservoir (in the Mississippi child, this was due to early ART’s curtailing the formation of the reservoir). The outcomes are consistent with mathematical modeling studies suggesting that significant shrinkage of the size of the reservoir can delay viral-load rebound, with very large reductions potentially equating to lifelong remission in the absence of ongoing ART. 
But while the three cases support the idea that limiting or reducing the viral reservoir – a key goal of the research effort – can be beneficial, so far no reservoir-reducing strategy has shown notable effects, let alone come close to the estimated 3-log reduction that occurred in the Boston patients as a result of stem cell transplantation. The mathematical models indicate that a 5-log drop or greater would be needed to achieve lifelong remission in the majority of HIV-positive individuals, so the research has some way to go if a cure is to be achieved by this strategy alone.
A key shared aspect of the Mississippi and Boston cases is that all three lacked detectable immune responses against HIV: in the child, this was due to ART’s suppressing HIV quickly after birth, before the developing immune system was significantly exposed to the virus; in the adults, it was because the stem cell transplants gave rise to a new donor-derived immune system that did not mount a response to HIV because suppressive ART was maintained throughout the procedures and for a long period afterward. So it’s important to appreciate that the periods of remission in these individuals were likely a consequence of reservoir depletion alone (as opposed to immunologic suppression of the virus) with the viral-load rebounds caused by the chance reactivation of a latently infected CD4+ T cell.
A more commonly described, less stringently defined type of remission (sometimes referred to as virological remission or posttreatment control) involves control of HIV viral load to very low but not necessarily completely undetectable levels in the absence of ART. The best known example of this phenomenon is the VISCONTI (Viro-Immunologic Sustained CONtrol after Treatment Interruption) cohort, consisting of 20 individuals treated during early infection who interrupted ART after a period of several years and have since maintained very low or undetectable viral loads for an average of nine years at the time of the last report.  There have also been various case reports over the years involving individuals who have maintained low or undetectable viral loads after ART interruption; typically, treatment was initiated during acute or early infection, but rare examples in chronic infection exist. [24, 25, 26, 27, 28, 29, 30]
While a relatively small HIV reservoir has been implicated in some of these cases, HIV-specific and innate immune responses are also present and may be contributing. Therefore, it’s possible that enhancing or rejuvenating antiviral immunity could lead to this intermediate type of remission while work continues toward the development of interventions capable of reducing the HIV reservoir to the dramatic extent mathematical models suggest is required to achieve a lifelong cure. Several of the trials listed in table 1 are exploring compounds whose mechanisms of action may have immunologic components, and several trials combining latency-reversing agents with therapeutic vaccines are under way or imminent.
A related thread of research is attempting to identify biomarkers that predict a delay in viral load rebound after ART interruption, which would allow candidate therapeutic approaches to be assessed without necessarily requiring study participants to stop treatment. A number of retrospective analyses presented or published over the past year have reported that levels of HIV DNA showed significant associations with time to viral-load rebound  or viral-load set point  in past clinical trials involving ART interruption. A forthcoming AIDS Clinical Trials Group (ACTG) study (ACTG A5345) plans to prospectively assess whether HIV reservoir measurements can predict the pace of viral-load recrudescence during a carefully monitored break from ART.
The ongoing efforts to define the parameters and predictors of ART-free remission form a backdrop to the entire cure research portfolio.
HIV Remission and Health
One of the challenges in defining remission is that there is evidence that even very low levels of HIV can have negative health consequences. Elite controllers, who naturally control viral load to low or undetectable levels in the absence of treatment, were at one time thought to experience no HIV-related illnesses. But in recent years it has been discovered that elite controllers can show elevated levels of immune activation and inflammation compared with HIV-negative individuals and are not completely protected from eventual CD4+ T-cell decline and progression to AIDS. [33, 34] A recent study reported that elite controllers are at increased risk of hospitalization compared with HIV-positive individuals on ART, particularly due to cardiovascular disease,  although the extent to which differences in other risk factors (such as smoking) may have contributed is not entirely clear. 
If elite controllers are at increased risk of illness compared with their HIV-negative counterparts or HIV-positive people on ART, it raises an important question: what degree of HIV control can actually be considered synonymous with disease-free remission?
The members of the VISCONTI cohort are reported to be healthy, but no one has attempted to prospectively compare the health of posttreatment controllers with HIV-positive people on ART and HIV-negative individuals (such a study would likely be very difficult to conduct given the small numbers). The issue is further complicated by the spectrum of HIV activity that may or may not be detectable in cases described as examples of remission, posttreatment control, or functional cure; this can range from trace amounts of viral genetic material without evidence of replication-competent virus to readily detectable but very low viral load (e.g., <50 copies/mL). There is reason to hope that the extreme low end of this spectrum would be associated with a lack of negative health consequences, but this has not been formally proved. Until these uncertainties are resolved, it should be borne in mind that the terminology used in cure research is not fully clarified, even though it is now quite common for media stories and company press releases to invoke terms like functional cure.
Histone Deacetylase (HDAC) Inhibitors
The research group of Ole Søgaard at the University of Aarhus in Denmark continues to pioneer the study of candidate latency-reversing agents in humans. These compounds aim to activate the dormant HIV in latently infected memory CD4+ T cells, which constitute the major reservoir of virus in individuals on ART.  Results from a clinical trial of the HDAC inhibitor panobinostat in HIV-positive individuals showed significant induction of HIV RNA expression,  and a genetic analysis by Sarah Palmer indicates that the drug activated a diverse pool of latent viruses.  Consistent with previously published laboratory research,  induction of HIV RNA expression did not lead to a measurable depletion of the HIV reservoir overall.
Four out of the 15 trial participants experienced a persistent decline in HIV DNA levels, ranging from 67% to 84%, and this correlated with a slightly longer time to viral-load rebound during an analytical ART interruption. An analysis presented as a poster by Martin Tolstrup at the 2014 International AIDS Conference suggested that this outcome may have been linked to innate immunity – particularly enhanced natural killer cell activity  – but due to the small subset of participants involved the results can be viewed only as exploratory.
Additional findings from the panobinostat trial were that no activation of HIV or inflammation was detectable in the cerebrospinal fluid;  cerebrospinal fluid was analyzed due to concerns that latency-reversing agents might provoke virus-associated damage to the brain. In a separate paper, the researchers reported that the drug significantly reduced biomarkers of inflammation and cardiovascular disease in the blood, leading to the suggestion that it might have role as an anti-inflammatory agent. 
Also at the 2014 International AIDS Conference, Søgaard presented preliminary results from an ongoing trial of the HDAC inhibitor romidepsin  (also currently under study at the ACTG). The results demonstrated induction of HIV RNA to levels detectable using a clinical viral-load test (>20 copies/mL and up to a little over 100 copies/mL in some cases), which has not been documented with any other latency-reversing agent to date. As in other HDAC inhibitor trials, no overall change in HIV DNA or other reservoir measures was observed.
No serious adverse events were documented in the panobinostat or romidepsin trials (side effects were primarily fatigue and gastrointestinal symptoms), although concerns have been raised about the unknown implications of long-term changes in gene expression associated with the receipt of HDAC inhibitors.  No evidence of an inhibitory effect of panobinostat or romidepsin on HIV-specific CD8+ T-cell responses was observed,  which a previously published laboratory study had suggested might be a problem. 
A second part of the romidepsin trial is now testing whether the addition of the therapeutic HIV vaccine candidate Vacc-4x (consisting of several conserved HIV Gag peptides) can invoke immune responses capable of eliminating latently infected CD4+ T cells that are induced to express HIV.
Other combinations of HDAC inhibitors and therapeutic HIV vaccines are also being explored in trials. Researchers at CARE plan to marry the HDAC inhibitor vorinostat with AGS-004, a dendritic cell-based vaccine that incorporates HIV antigens derived from viral RNA sampled from the intended recipient.  In the United Kingdom, the Research In Viral Eradication of HIV Reservoirs (RIVER) trial aims to evaluate an HDAC inhibitor along with chimpanzee adenovirus and modified vaccinia Ankara strain (MVA) vaccine vectors encoding HIV antigens selected based on their conservation among diverse viruses.
The drug disulfiram, better known by its trade name, Antabuse, is approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcoholism. The potential HIV latency-reversing activity of disulfiram was first identified in a laboratory screen conducted by Robert Siliciano’s research group at Johns Hopkins,  and a small pilot study was later conducted at the University of California, San Francisco (UCSF).  Data from a larger dose-escalation trial recently presented by Steven Deeks of UCSF revealed significant increases in levels of cell-associated HIV RNA, along with a postadministration increase in plasma HIV RNA of around twofold in recipients of the highest dose, 2,000 mg/day.  Although there has been some variability in the results, there is interest in continuing to study disulfiram’s latency-reversing potential due to its extensive safety record.
Scientists in Spain have completed a small study of disulfiram at a dose of 1,000 mg/day in combination with a therapeutic HIV vaccine, MVA-B (an MVA vector encoding clade B HIV antigens). The vaccine successfully induced HIV Gag-specific T-cell responses and was associated with a very slight delay in viral-load rebound during an analytic ART interruption. Viral-load rebound kinetics were not significantly different among participants receiving disulfiram in addition to MVA-B, and no reduction in HIV DNA levels was observed. 
Toll-Like Receptor (TLR) Agonists
TLRs are involved in the recognition of particular patterns common to pathogenic organisms and play a role in the induction of innate and adaptive immunity. Stimulation of TLRs with agonist molecules can have adjuvant and therapeutic effects by modulating the immune response, and several TLR agonists have been reported to activate latent HIV in vitro. [53, 54] There is particular interest in the possibility of a dual mechanism of action, as TLR agonists have also been reported to enhance natural killer and CD8+ T-cell activity against HIV. 
Two widely publicized presentations at the 2015 Conference on Retroviruses and Opportunistic Infections describe the latency-reversing capacity of GS-9620, a TLR-7 agonist developed by Gilead Sciences. In a study in SIV-infected macaques on ART, GS-9620 caused transient viral-load increases to detectable levels at the highest dose administered. Evidence of increased natural killer cell and CD8+ T-cell activation was also seen, and levels of HIV DNA declined significantly in three of four animals, in both blood and tissues.  A separate poster presentation reported that GS-9620 activated latent HIV in CD4+ T cells isolated from HIV-positive individuals on ART.  Clinical trials in hepatitis B and C have found GS-9620 to be safe, [58, 59] and a phase I exploration of safety and activity in HIV-positive individuals is under way (regrettably, Gilead Sciences has not registered the trial at clinicaltrials.gov).
In addition to its work with HDAC inhibitors and therapeutic vaccination, Søgaard’s group has recently launched a trial of a TLR-9 agonist to study its effects on the HIV reservoir. The rationale derives from an exploratory analysis of a trial of a pneumococcal vaccine in HIV-positive individuals on ART in which one arm received a TLR-9 agonist as an adjuvant; levels of HIV DNA among the participants in this arm declined significantly, and this correlated with increases in markers associated with improved CD8+ T-cell function. 
An ongoing trial at Rockefeller University is investigating poly-ICLC, a TLR-3 agonist more typically used as a vaccine adjuvant.
Interleukin-15 (IL-15) Superagonist ALT-803
Agents that may have a dual mechanism of action – both reversing HIV latency and enhancing immune responses with the potential to eliminate virus-infected cells – have emerged as a theme this year. Among them is the cytokine IL-15, which has been shown to induce HIV production by latently infected CD4+ T cells  and promote natural killer cell and CD8+ T-cell activity.  ALT-803, also known as an IL-15 superagonist, is a modified version of the cytokine with enhanced potency. Recent studies of ALT-803 indicate that it can activate natural killer cells, leading to inhibition of HIV in humanized mice.  In laboratory experiments, ALT-803 was found to both stimulate expression of HIV antigens by latently infected CD4+ T cells and enhance their killing by HIV-specific CD8+ T cells.  A pilot study of ALT-803 in HIV-positive individuals on ART is due to start soon at the University of Minnesota.
Bryostatin-1/Protein Kinase C (PKC) Agonists
Bryostatin-1 belongs to a class of compounds known as PKC agonists. Laboratory studies have shown that PKC agonists can induce HIV production by latently infected CD4+ T cells  and work synergistically with HDAC inhibitors to achieve levels of latency-reversing activity close to those observed with maximal CD4+ T-cell activation. [66, 67] Bryostatin-1 has also been reported to interact with TLR-4 and stimulate production of chemokines capable of inhibiting HIV.  There are concerns about the potential toxicity of bryostatin-1, which has caused severe myalgias and other grade 3 and 4 adverse events in cancer trials,  but a small trial involving low doses is ongoing in Spain. The company supplying the drug, Aphios Corporation, is considering developing a combination latency-reversing agent incorporating bryostatin-1 (or a similar analogue) and an HDAC inhibitor. 
Another PKC agonist drawing interest is Ingenol-B, an extract from the sap of the tropical shrub Euphorbia tirucalli. Several research laboratories have reported that it has latency-reversing activity, [71, 72, 73] and there is evidence to suggest that it may be less prone to cause toxicity than other PKC agonists. Clinical trials are in the planning stages.
Broadly Neutralizing Antibodies
New technologies have facilitated the discovery of an increasing number of antibodies capable of broadly neutralizing a diverse array of HIV isolates from across the globe, many with great potency (robust inhibition of HIV is achieved at relatively low antibody concentrations). [74, 75, 76] Tens of thousands of HIV-specific B cells can now be sampled from HIV-positive individuals and the antibodies they are producing fished from each individual cell and tested for their ability to inhibit viral replication. The broadly neutralizing antibodies (bNAbs) identified with this approach do not necessarily benefit the person they are sampled from, likely due in part to the complex swarm of diverse HIV variants circulating in chronically infected individuals, and the titers of the bNAbs being low compared to the amount of virus present. But the potency and breadth of neutralization of the new generation of bNAbs suggest that they could be beneficial when delivered intravenously or subcutaneously in both preventive and therapeutic contexts (Preventive Technologies).
For cure researchers, there is particular interest in the potential of bNAbs to promote destruction of HIV-infected cells via antibody-mediated cellular cytotoxicity or antibody-mediated cellular phagocytosis.  These effector functions involve the binding of the antibody to HIV antigens being expressed by infected cells, followed by the recruitment of natural killer cells or monocytes to destroy the cell (the recruitment is accomplished by a part of the antibody structure known as the Fc region, which interacts with Fc receptors on the effector cells). A study in humanized mice has provided evidence that this type of antibody-mediated activity can work in concert with latency-reversing agents to diminish the HIV reservoir. 
Several potent bNAbs are now being manufactured and tested in clinical trials, and this year saw the publication of results from a phase I evaluation of the bNAb 3BNC117 in HIV-positive individuals.  At the highest of the four doses administered (30 mg/kg), a single intravenous infusion of 3BNC117 led to a decline in viral load ranging from 0.8 to 2.5 logs, with four of eight recipients remaining below baseline at the last reported follow-up (day 56 postinfusion). There was evidence of 3BNC117-resistant HIV emerging in some participants, and one individual showed high-level resistance to the antibody at baseline. The investigators are currently analyzing whether any recipients developed immune responses against the 3BNC117 antibody; those results are pending.
The confirmation that bNAbs are active against HIV in humans presages a significant expansion of research in this area. VRC01, a bNAb developed by the NIH Vaccine Research Center (VRC), is already undergoing testing (delivered intravenously or subcutaneously)  in both HIV-positive and HIV-negative individuals, and several new clinical trials are imminent; these include an assessment of effects on the HIV reservoir and on viral-load rebound after ART interruption. The U.S. Military HIV Research Program will soon launch a study of VRC01 in Thai individuals with acute HIV infection.  The VRC has begun manufacture of a longer-acting formulation of VRC01 (VRC01-LS) and an additional long-acting bNAb, VRC07-523-LS.
The research group of Dan Barouch at the Beth Israel Deaconess Medical Center is on the verge of initiating trials of the bNAb PGT121 after obtaining promising results in macaque experiments.  If all goes well, future plans include combination studies with other bNAbs and latency-reversing agents. 
The researchers responsible for the 3BNC117 trial, led by Sarah Schlesinger at Rockefeller University, are working on several protocols that aim to test the effects of 3BNC117 on the HIV reservoir (either alone or in combination with a latency-reversing agent), the impact on viral rebound after ART interruption, and efficacy in combination with the bNAb 10-1074. 
An alternative approach to therapeutically exploiting immune responses against HIV is to administer CD8+ T cells targeting the virus. The CD8+ T cells are extracted from the intended recipient, stimulated with HIV antigens and expanded in the laboratory, and then reinfused. David Margolis and colleagues from CARE and the University of North Carolina at Chapel Hill are pursuing this strategy – which they have named HIV-1 Antigen Expanded Specific T Cell Therapy (HXTC)  – as a means to target the HIV reservoir, and an initial phase I trial investigating safety and efficacy has begun. In laboratory studies, HIV-specific CD8+ T cells generated by their method were able to kill latently infected CD4+ T cells exposed to the latency-reversing HDAC inhibitor vorinostat.  Infusions of autologous HIV-specific CD8+ T cells are also being studied in an ongoing trial led by Yong-Tao Sun of the Tangdu Hospital, Fourth Military Medical University in Xi’an, China.
Mammalian Target of Rapamycin (mTOR) Inhibitors
Drugs that inhibit the cellular protein mTOR are under investigation in two trials. The effects of mTOR inhibitors are complex, involving both immune-suppressive and immune-enhancing activity. In a retrospective study of HIV-positive individuals who had undergone kidney transplantation, receipt of the mTOR inhibitor sirolimus was associated with significantly reduced levels of HIV DNA.  The ACTG is soon to launch a pilot study to prospectively measure the impact of the drug on the HIV reservoir.
Researchers at UCSF plan to conduct a trial that will add six months of everolimus, a derivative of sirolimus, to the regimens of HIV-positive individuals who have received kidney or liver transplants. The effect on the HIV reservoir will be assessed at several times during and after receipt of the drug.
A development in gene therapy that made the news earlier this year was the approval by the FDA of a clinical trial involving genetic modification of stem cells. The project involves collaboration between researchers from City of Hope Medical Center in Los Angeles, the Keck School of Medicine at the University of Southern California, and Sangamo BioSciences, with support from the California Institute for Regenerative Medicine (CIRM). Stem cells will be extracted from individuals, treated with Sangamo’s zinc finger nuclease technology to disrupt the CCR5 gene, and then reinfused with the aim of generating CCR5-negative immune cells resistant to HIV. According to a press release from CIRM, the initial study population will be HIV-positive individuals responding poorly to ART.  Although some of the headlines described the approach as a “functional cure”  or “potential cure,”  this is in fact only an exploratory study, and it is wildly premature to suggest that it could be curative; previous trials involving genetic modification of stem cells have generated only low levels of gene-modified CD4+ T cells. 
The Fred Hutchinson Cancer Research Center has listed two new gene therapy trials for HIV-positive individuals requiring stem cell transplants for lymphoma. One protocol will genetically modify stem cells with a vector that disrupts CCR5 and encodes the HIV fusion inhibitor protein C46. The vector also encodes a gene (P140K) that enables the engraftment of gene-modified cells to be promoted by the administration of a combination of drugs, O6-benzylguanine and carmustine.  Analytic ART interruptions may be performed if sufficient levels of gene-modified cells are achieved. The other trial will alter stem cells with Cal-1, a lentiviral vector developed by Calimmune that encodes a short hairpin RNA that inhibits expression of CCR5 and C46. 
Research continues into the use of the Sangamo BioSciences technology to genetically modify CD4+ T cells ex vivo. The CD4+ T cells are extracted from HIV-positive individuals, exposed to the zinc finger nuclease to disrupt the CCR5 gene, then expanded and reinfused. In studies published and presented to date, [94, 95] an adenovirus vector was used to deliver the zinc finger nuclease into the CD4+ T cells during the process. The company is now testing a different and potentially more efficient approach in which messenger RNA encoding the zinc finger nuclease is used instead of an adenovirus vector. Over the past year, two clinical trials have opened that will deliver CD4+ T cells modified with this method; both are using transient administration of cyclophosphamide prior to the infusion to enhance the engraftment of the altered cells.
Pediatric Cure Research
In addition to the IMPAACT P1115 clinical trial mentioned in the introduction, there are three other new studies investigating the effect of ART on the HIV reservoir in the context of mother-to-child transmission. The Early Pediatric Initiation: Canadian Child Cure Cohort Study (EPIC4) is an observational cohort study being conducted by Hugo Soudeyns and colleagues under the aegis of the recently established Canadian HIV Cure Enterprise. The aim is to study the HIV reservoir and biomarkers of disease pathogenesis in children and adults who acquired infection at birth and have had varied treatment histories.
The Latency and Early Neonatal Provision of Antiretroviral Drugs (LEOPARD) clinical trial is being led by Louise Kuhn at Columbia University and plans to investigate ART initiated within 48 hours of birth in 60 vertically infected infants in South Africa. The Harvard School of Public Health is sponsoring Early Infant HIV Treatment (EIT) in Botswana, which will assess early ART in two cohorts of infants, one infected antepartum (started on ART within seven days of birth) and the other peripartum (started on ART within 57 days of birth).
New therapeutic vaccines undergoing evaluation include iHIVARNA-01, which uses messenger RNA to deliver HIV antigens along with TriMix, an adjuvant cocktail consisting of three proteins involved in the activation of antigen-presenting cells: CD40L, CD70, and TLR4. The first clinical trial is being launched as part of a collaborative effort involving multiple European institutions coordinated by Felipe García of Barcelona’s Institut d’Investigacions Biomèdiques August Pi i Sunyer, with funding support from the European Commission. 
Researchers at Imperial College London have initiated a new trial of FIT Biotech’s GTU-MultiHIV B clade naked DNA vaccine in HIV-positive individuals on ART. Two different routes of administration will be compared: transcutaneous, or intramuscular with electroporation (which delivers a brief electrical pulse to enhance cellular uptake of the DNA).
Recent published results include those from a completed trial of Barbara Ensoli’s HIV Tat protein vaccine, which has been the subject of some controversy over the years, with questions having been raised about the appropriateness of Italian government funding for the research.  Ensoli and colleagues’ paper, published in the open-access journal Retrovirology, reports that the vaccine induced Tat-specific antibody responses and that recipients showed a lowering of HIV DNA levels.  However, the trial did not include a placebo control group; instead, comparisons were made with a separate parallel cohort, and this makes the data difficult to interpret. Results from a randomized clinical trial conducted in South Africa are pending.
At the HIV Research 4 Prevention conference in Cape Town in October 2014, Harriet Robinson from GeoVax presented results from a small therapeutic trial of the company’s DNA/MVA prime-boost HIV vaccine approach. A total of nine individuals who had started ART within 18 months of seroconversion received the DNA/MVA regimen and underwent a 12-week analytic ART interruption. HIV-specific CD8+ T cells were increased in the majority of participants, but viral-load rebound occurred in all individuals after ART cessation. The levels of HIV viral load were somewhat lower at the end of the ART interruption compared with the pre-ART baseline in five participants, but there was no suggestion of vaccination leading to durable control. A clinical trial is now being planned that will combine the DNA/MVA vaccine with a latency-reversing agent. 
|interleukin-7 (IL-7)||Cytokine||French National Agency for Research on AIDS and Viral Hepatitis (ANRS)/Cognate Biosciences||Phase II|
|losartan||Angiotensin II receptor antagonist, anti-inflammatory||Minneapolis Medical Research Foundation||Phase II|
|lubiprostone||Apical lumen ClC-2 chloride channel activator||Ruth M. Rothstein CORE Center/Chicago Developmental Center for AIDS Research||Phase II|
|methotrexate (low-dose)||Anti-inflammatory||NIAID||Phase II|
|metformin||Biguanide antidiabetic||University of Hawaii/National Institute of General Medical Sciences||Phase II|
|niacin||Vitamin B3||McGill University Health Center/Canadian Institutes of Health Research (CIHR) Canadian HIV Trials Network||Phase II|
|VSL#3||Probiotic||Virginia Commonwealth University/Bill & Melinda Gates Foundation, University Health Network, Toronto/CIHR Canadian HIV Trials Network||Phase II|
|dipyridamole||Phosphodiesterase type 5 inhibitor, anti-inflammatory||Sharon Riddler, University of Pittsburgh/NIAID||Phase I/II|
|Mesenchymal stem cells||Allogenic adult mesenchymal stem cells from adipose tissue||Iniciativa Andaluza en Terapias Avanzadas – Fundación Pública Andaluza Progreso y Salud||Phase I//II|
|Tripterygium wilfordii Hook F||Traditional Chinese medicine, anti-inflammatory||Beijing 302 Hospital/Peking Union Medical College||Phase I/II|
|Umbilical cord mesenchymal stem cells||Adult stem cells originating from the mesenchymal and connective tissues||Beijing 302 Hospital||Phase I//II|
|vorapaxar||Thrombin receptor (PAR-1) antagonist||Kirby Institute/NIAID/University of Minnesota – Clinical and Translational Science Institute/University of Melbourne/Merck||Phase I/II|
|aprepitant||Neurokinin 1 receptor antagonist||University of Pennsylvania||Phase I|
|HLA-B*57 cell transfer||Cell infusion||NIH Clinical Center||Phase I|
|hydroxychloroquine||Antimalarial, antirheumatic, anti-inflammatory||St Stephens AIDS Trust||Phase I|
As outlined in the introduction to this chapter, very little is trickling through the immune-based therapy pipeline. A study of the antifibrotic drug pirfenidone in SIV-infected macaques offered support for the idea that repairing lymph node fibrosis, a type of scarring damage that occurs in HIV infection, might promote CD4+ T-cell reconstitution.  The immunologic effects of a similar drug, losartan, are being tested in an ongoing clinical trial for HIV-positive individuals on ART at the University of Minnesota. 
In a small trial conducted in China, therapeutic administration of umbilical cord-derived mesenchymal stem cells was reported to increase CD4+ T cells and decrease markers of immune activation and inflammation in INRs.  An additional trial in INRs is now being launched in Spain; it differs somewhat from the research in China because the mesenchymal stem cells are sourced from adipose (fatty) tissue rather than umbilical cords. 
Another relatively unconventional therapy is Tripterygium wilfordii Hook F, an extract from a vine used in traditional Chinese medicine. A paper published earlier this year reported that administration to INRs in a small pilot study was associated with an increase in CD4+ T-cell counts;  a larger randomized trial that aims to enroll 60 people is under way.  An extract of Tripterygium wilfordii is also being studied in China for its effects on the HIV reservoir (see table 1).
Interventions with potential anti-inflammatory effects continue to generate interest. A trial with sites in Australia and the United States will test the Merck drug vorapaxar for its effects on D-dimer (a coagulation biomarker that has been associated with mortality in HIV infection)  and markers of immune activation.  Aprepitant (brand name Emend) is an FDA-approved antiemetic that has been reported to have anti-inflammatory properties in HIV-positive individuals during a short two-week course of treatment.  A follow-up trial is now evaluating whether ritonavir-containing ART regimens can increase aprepitant levels and enhance the drug’s impact on inflammatory biomarkers over four weeks of administration. 
Results from a double-blind, randomized, placebo-controlled trial of the probiotic Saccharomyces boulardii were published in March 2015.  A total of 44 HIV-positive individuals on ART were enrolled, and significant declines in lipopolysaccharide-binding protein (LBP) and IL-6 were documented in the probiotic recipients. LBP is a marker of microbial translocation (leakage of normally beneficial bacteria from the gut into the systemic circulation), and IL-6 is an inflammatory biomarker that has been associated with the risk of death in HIV-positive people.  Three new studies of the probiotic VSL#3 are being undertaken: one sponsored by Virginia Commonwealth University and the Bill & Melinda Gates Foundation that is recruiting Malian women not yet on ART  and two by the University Health Network, Toronto, and the Canadian HIV Trials Network – one involving individuals starting ART  and the other INRs with CD4+ T-cell counts less than 350/mm3 despite two years or more of ART. 
Hopes that the anti-inflammatory properties of chloroquine might be of benefit to INRs appear to be fading. Results from two clinical trials have become available: researchers in Canada added chloroquine to ART in INRs and found no significant changes in T-cell counts or markers of immune activation and inflammation except for an increase in alpha interferon.  An ACTG study of chloroquine in HIV-positive individuals either on or off ART documented no significant differences in immune activation or CD4+ T-cell counts; these results are unpublished but available at clinicaltrials.gov. 
The expansion of research toward an HIV cure has continued over the past year. The growing number of clinical trials can be viewed as the tip of the iceberg; below the waterline lies formative basic research and work in animal models aiming to fully delineate the HIV reservoir and refine how to measure and, ultimately, eliminate it. Prominent among the approaches being translated from the basic to clinical realms this year are those with a potential dual mechanism of action: reversing HIV latency and stimulating immune responses against virus-infected cells.
The growing number of cure-related projects and collaborations globally is encouraging, but the decline in funding for the NIH – the world’s largest funder of scientific research – is a major concern that must be addressed. As the field increasingly draws media attention, a broader dialogue is needed in order to reach consensus about how the goals of cure research and the terminology are characterized and communicated; the concept of HIV remission is increasingly invoked but is not yet clearly defined.
While the cure research pipeline is swelling, prospects for immune-based adjuncts to ART – interventions for which there remains a need – have dimmed in recent years. This is not due to lack of interest from scientists and clinicians, who are still pursuing small-scale studies of a range of possible therapies, but there is little sign of the industry support that might thrust an approach with promise through the pipeline. On a more hopeful note, although only tangentially related to immune-based therapy, the REPRIEVE trial of statin treatment may offer insight into the feasibility of conducting large-scale clinical evaluations of add-ons to ART.
Unless noted otherwise, all links were accessed on June 8, 2015.
CROI: Conference on Retroviruses and Opportunistic Infections
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