Preventive Technologies, Immune-Based and Gene Therapies and Research Toward a Cure

Anti-Inflammatories

The antimalarial drugs chloroquine phosphate and hydroxychloroquine are being assessed for their potential to reduce immune activation and improve CD4 T cell recovery in individuals on ART. A very small pilot trial of chloroquine phosphate that was published last year reported significant reductions in markers of immune activation over two months of treatment (Murray 2010).

Mesalamine is an oral anti-inflammatory drug that acts particularly on the cells of the gut (Iacucci 2010), and the US Food and Drug Administration has approved it for the treatment of ulcerative colitis, proctitis, and proctosigmoiditis. The research group of Steve Deeks at the University of California-San Francisco (UCSF) is conducting a small study to ascertain if mesalamine can reduce inflammation levels in HIV-positive people on ART. The study is motivated by evidence that leakage of normally friendly gut bacteria into systemic circulation (microbial translocation) contributes to immune activation in HIV infection (Brenchley 2006) and is associated with poor immune reconstitution on ART (Marchetti 2008). The same research group has also probed the contribution of CMV co-infection to immune activation in people on ART by conducting a trial of the anti-CMV drug valganciclovir. The study, now published, found that markers of activation on CD8 T cells were significantly reduced by this intervention, suggesting suppression of CMV replication could have benefits in co-infected people with HIV (Hunt 2011a). Unfortunately the toxicity profile of valganciclovir makes it a poor candidate for chronic use, so safer anti-CMV therapies will be needed in order for this potential lead to be followed.

A number of investigators are evaluating whether the approved CCR5 inhibitor maraviroc can dampen immune activation and enhance immune reconstitution. Results from two trials presented at the Conference on Retroviruses and Opportunistic Infections in 2011 were not particularly encouraging, however. In one uncontrolled, single-arm experiment markers of immune activation were reported decrease (Wilkin 2011), but in the other randomized placebo-controlled study these markers increased in blood and gut samples (Hunt 2011b). In neither case did CD4 T cell counts increase significantly.

Two new clinical trials are looking at the anti-inflammatory effects of the pain medication etoricoxib and the lipid lowering agent simvastatin in HIV, respectively. The etoricoxib trial is enrolling people naive to ART due to a prior study finding that the drug reduced immune activation and improved T cell function in individuals for whom ART was not indicated based on European guidelines (Pettersen 2011). Researchers at the University of Pennsylvania are recruiting individuals off ART for their study of simvastatin, in order to assess if the drug can reduce the monocyte inflammation and inflammatory cytokine production that has been linked to brain disease in HIV.

Cell Infusion and Gene Therapies

In addition to being involved in the Sangamo Biosciences trials described in the section on research toward a cure, Carl June's research group at the University of Pennsylvania is evaluating a different gene therapy that modifies CD8 T cells ex vivo, equipping them with a T cell receptor (TCR) that is particularly adept at recognizing HIV-infected cells (Varela-Rohena 2008). The souped-up CD8 T cells are then expanded and re-infused back into the individual. The ultimate goal is to combine both CD4 and CD8 T cell gene therapy approaches in order to enhance the ability of both subsets to deal with HIV.

Last year, researcher John Rossi from City of Hope in Los Angeles published results from a phase I trial of a combined gene therapy approach in HIV-infected individuals undergoing hematopoietic stem cell (HSC) transplantation for AIDS-related lymphoma (DiGiusto 2010). Genes encoding three different anti-HIV RNA molecules were introduced into a subset of transplanted HSCs in four individuals, and long-term persistence in multiple cell lineages was demonstrated, albeit at very low levels. Although no therapeutic effect could be demonstrated, the study offers evidence that the concept is feasible. Rossi's group is now collaborating with Paula Cannon at the University of California at Los Angeles (UCLA) and Sangamo Biosciences to study the deletion of the CCR5 gene in HSCs, in the same setting of AIDS-related lymphoma.

IL-7

The cytokine IL-7 plays a key role in supporting T-cell development and the proliferation and survival of naive and memory T-cells. Results from two phase I trials of IL-7 in people with HIV reported substantial increases in CD4 and CD8 T-cell counts even at the lowest dose (Levy 2009; Sereti 2009). The cytokine was well tolerated. A new glycosylated form of IL-7 that allows less frequent administration is currently in phase II trials. The manufacturer is a French company named Cytheris. The ACTG is considering the possibility of studying the clinical effects of IL-7 in individuals with poor CD4 recovery despite HIV suppression.

The ability of IL-7 to reduce HIV reservoirs is also under investigation, but there is debate regarding its potential in this setting; while viral load blips were observed in one phase I study (Sereti 2009), it has been argued that the source of this virus was not long-lived reservoirs (Imamichi 2011). Furthermore, it has been shown that under some circumstances IL-7 may expand the number of latently HIV-infected CD4 T cells by stimulating their division (Chomont 2009).

Therapeutic Vaccines

The proposal that therapeutic vaccination might enhance the immune response to HIV was floated soon after the virus was first discovered. But clinical trials of a variety of candidates proved consistently disappointing, with no clear evidence of benefit. The most publicized was a large clinical endpoint study of Jonas Salk's candidate, Remune, which showed no significant differences in health outcomes between vaccine and placebo (Khan 2000). The arrival of combination ART lessened the need for a therapeutic vaccine, but also opened up a window of opportunity because it became possible to try and induce new immune responses to HIV without interference from the potentially immune-suppressive effects of ongoing viral replication. An array of therapeutic vaccines are undergoing testing in this context.

Scientists at the University of Barcelona published the first data on their dendritic cellbased approach earlier this year (Garcia 2011). A small but statistically significant viral load reduction was observed in the vaccine recipients, along with some evidence for an inverse association between HIV-specific T cell responses and viral load. The company Argos Therapeutics is also developing a dendritic cell-based therapeutic vaccine, with the twist that it is "personalized" by loading the cells with viral RNA from the person who is going to receive the vaccine; the goal is to induce immune responses that are exquisitely specific to each individual's HIV infection (Routy 2010).

Italian researcher Barbara Ensoli at the National AIDS Center at the Istituto Superiore di Sanità in Rome continues to plug away with studies of a therapeutic Tat protein vaccine that has been in development for over a decade now. Ensoli and colleagues took the dubious step of publishing interim results from an ongoing trial in people on ART, claiming a variety of beneficial effects associated with vaccination, including reductions in markers of immune activation (Ensoli 2010).

A novel approach to therapeutic immunization that recently entered human testing is Opal Immunotherapy. Developed by Stephen Kent's research group at the University of Melbourne, it involves repurposing sets of overlapping peptides derived from HIV that are normally only used in laboratories to measure T cell responses against the virus. Kent had the idea to try and use the peptides as a vaccine by mixing them with either peripheral blood mononuclear cells (PBMC) or whole blood, then infusing this mixture. Studies in SIV-infected macaques have shown some promise (De Rose 2008) and a phase I trial is now underway.

An alternate strategy being pursued by some therapeutic vaccine manufacturers is immunization of HIV-positive people prior to any significant CD4 T-cell decline, with the aim of delaying the need for ART. At the 2010 International AIDS Conference, results from a 60-person randomized controlled study of this type were reported, showing that a DNA vaccine manufactured by FIT Biotech lowered viral load by around half a log after two years of follow up. A small but statistically significant increase in CD4 T cell counts was also observed (Vardas 2010).

The largest pharmaceutical company involved in this research area is GlaxoSmithKline. Their vaccine candidate, obscurely designated 732462, consists of a fusion protein including several HIV antigens (p24, p17, reverse transcriptase and Nef) in a proprietary adjuvant, AS01B. GSK is conducting a phase II trial exploring the potential for immunization to delay the need for ART.

Conclusion

As incremental as it may be, there is no doubt that significant progress has occurred over the past few years. Until quite recently, there was no evidence of efficacy from any vaccine, microbicide, or PrEP trial. But the investment in research is starting to pay off, and while it may be frustrating that no product is yet available, there is definitely light at the end of these pipelines.

For cure research, the shift from the laboratory to clinical trials is only just beginning. But there is already hope in the form of Timothy Brown, and an increasing demand for science to push beyond the ART-for-life paradigm that currently prevails. The rising profile of cure research is also providing a welcome opportunity for immune-based and gene therapies to emerge from relative obscurity and enter the mainstream.