Reviewing Strategies for Draining HIV Reservoirs

The April issue of Human Vaccines & Immunotherapeutics features an excellent open access review by Thomas Rasmussen and colleagues describing approaches to eliminating HIV reservoirs that are advancing into clinical trials.

Prominently featured are histone deacetylase (HDAC) inhibitors, which have emerged as lead candidates for liberating latent HIV from cellular lockdown. The paper offers detailed descriptions of the various HDAC inhibitors being studied—or considered for study—and notes that the authors, who are based at the University of Aarhus in Denmark, have launched a phase I trial of one such drug, panobinostat, in people with HIV. Also cited is their companion study in the January issue of the same journal (now available open access) that compares the activity of several HDAC inhibitors in clinical development. Among the less-discussed aspects of HDAC inhibitors that are highlighted in the review are the potential for both pro- and anti-inflammatory effects depending on the individual compound (the latter effect could conceivably be beneficial in HIV infection).

Since the review was published, additional relevant data has emerged from CROI: as mentioned in a previous post, results from Sharon Lewin’s trial of vorinostat were presented, and George Wei from Gilead Sciences gave a glimpse at the first in vitro data on romidepsin, reporting that it is 500 times more potent at reactivating latent HIV than vorinostat (the ACTG is now planning a phase I trial). Not all the news was positive, however: as discussed in an April 4th Nature Medicine news article by Elie Dolgin, Antony Cillo described study results indicating that HDAC inhibitors may only induce a small fraction of latently infected cells to produce viral proteins, possibly meaning that combinations of anti-latency approaches will be needed to comprehensively target HIV reservoirs.

Potentially supplementing the armamentarium are immune-based strategies such as those targeting toll-like receptors (TLRs). TLRs are involved in the recognition of pathogenic organisms and, as the review by Rasmussen and colleagues explains, there is evidence that compounds that stimulate TLRs (TLR agonists) can induce HIV expression by latently infected cells. They reference their own study of a TLR9 agonist named CPG 7909 as a pneumococcal vaccine adjuvant in people with HIV, that—in an example of scientific kismet—allowed them the opportunity to go back and investigate its effect on the latent HIV reservoir. The results were reported at CROI and, while exploratory, showed a significant mean reduction in HIV DNA levels of 12.6% after each immunization. The decline in HIV DNA correlated with an increase in HIV-specific CD8 T cells expressing CD107a (a marker for their release of cell-killing substances) and the chemokine MIP1β. This study was subsequently published on April 26 in the journal PLoS One. 

Other research groups are also looking at the anti-latency properties of TLR agonists. At CROI, Camille Novis from the laboratory of Alberto Bosque presented a poster showing that Pam3CSK4, which targets TLR2/1, was able to reactivate HIV from latently infected CD4 T cells without causing T cell activation. Romas Geleziunas has cited plans to study GS-9620, a TLR7 agonist, in several presentations describing the Gilead Sciences HIV eradication program (further details are included in his slides from the 2012 International Symposium HIV & Emerging Infectious Diseases).

The review by Rasmussen et al mentions the cytokine IL-7 as a possible immunotherapy to reduce HIV reservoirs, under evaluation in a trial named Eramune 01 at the time the paper was written. Results debuted at CROI in a poster and, disappointingly, IL-7 added to intensified antiretroviral therapy (ART) was not successful in reducing HIV DNA levels (there was some evidence it may have slightly increased levels due to causing transient proliferation of latently infected CD4 T cells). Despite this outcome, IL-7 had a beneficial impact on CD4 and CD8 T cell counts, as seen in prior studies, and remains the lead candidate for enhancing immune reconstitution in individuals with poor CD4 recovery despite HIV suppression by ART (in this population, the increased risk of morbidity and mortality is a far greater concern than small changes in HIV DNA levels).

The topic of targeting HIV reservoirs is the subject of another recent review by Christine Katlama and colleagues in The Lancet, but this paper is not open access and requires a subscription (although it may eventually appear in PubMed’s full text archive).  

Update 4/20/13: The April issue of Clinical Pharmacology & Therapeutics includes a free commentary on HIV cure research by Christine Durand and Charles Flexner, and the journal has also made a review on the subject from the January issue (by Kirston Barton, Brandon Burch, Natalia Soriano-Sarabia and David Margolis) available open access. Abstracts and links added below.  

Update 4/29/13: Sadly, it seems that one of the authors of the Human Vaccines & Immunotherapeutics review, Dr. Ole Søgaard, has rather shot himself in the foot by contributing to a wildly irresponsible article in the UK newspaper the Daily Telegraph regarding his group's ongoing research. The article misstates the mechanism of action of HDAC inhibitors (stating that they "strip" HIV DNA from latently infected cells when, at best, they prompt the HIV DNA into transcribing proteins) and uncritically reports Dr. Søgaard's apparent confidence in the ability of panobinostat to reactivate latent HIV; as noted in the Nature Medicine news article linked to above, there are many outstanding questions regarding the ability of HDAC inhibitors to accomplish this task.

The Telegraph also mentions the use of immune-based therapies to prompt the killing of latently infected cells (assuming the cells are successfully induced to express HIV); my best guess is that, in the case of Dr. Søgaard's group, this is a reference to their data on the TLR9 agonist CPG 7909, although the article is unconscionably vague on this point. Also cited, again vaguely, are plans by Lucy Dorrell's research group in the UK to conduct a trial in which HDAC inhibition is combined with therapeutic vaccination. This research is undoubtedly very important but for the article to suggest that it means that scientists are on the brink of an HIV cure is shockingly erroneous and misleading. The promise of these approaches can only be evaluated when the results of the studies become available. Since the trials combining HDAC inhibitors and immune-based therapies (whether TLR agonists or therapeutic vaccines) have yet to start it is extremely unlikely that the data will be available in "months" as the subhead of the article claims.

Inevitably, the Daily Telegraph piece has triggered the media equivalent of a game of telephone in which other outlets rehash the story while managing to mangle the facts further (e.g. see the Daily Mail, which elevates the mistatement about how HDAC inhibitors work into a subhead: "Danish scientists using a technique which strips HIV virus from human DNA"). 

Update 5/2/13: The Daily Telegraph article has now been edited to correct the erroneous and misleading statements in the subhead and the body of the story (the title, however, currently remains). For example, "expecting results" in the opening para has been changed to "hoping for results," and several quotes have been modified to highlight the uncertainty regarding what proportion of the latent HIV reservoir can be activated by HDAC inhibitors. The suggestion that participants in the panobinostat trial might be cured of HIV infection has also been removed. 

Additonally, Dr. Søgaard has kindly posted a comment below that addresses the article and clarifies the views of his research group. 

Update 5/3/13: Hopefully the last update on this, the Aarhus University Hospital has now issued a formal correction to the Telegraph story. And the Telegraph has changed the title of the article to "Scientists' hope for HIV cure."

Hum Vaccin Immunother. 2013 Apr 1;9(4). [Epub ahead of print]

Eliminating the latent HIV reservoir by reactivation strategies: Advancing to clinical trials.

Rasmussen TA, Tolstrup M, Winckelmann A, Ostergaard L, Søgaard OS.

Department of Infectious Diseases; Aarhus University Hospital; Denmark.

Abstract

Combination antiretroviral therapy (cART) has transformed HIV from a deadly to a chronic disease, but HIV patients are still burdened with excess morbidity and mortality, long-term toxicities from cART, stigmatization, and insufficient access to cART worldwide. Thus, a cure for HIV would have enormous impact on society as well as the individual. As the complexity and mechanisms of HIV persistence during therapy are being unraveled, new therapeutic targets for HIV eradication are discovered. Substances that activate HIV production in the latently infected cells have recently received much attention. By turning on expression of latent HIV proviruses, reactivation strategies could contribute to the eradication HIV infection. Compounds that are currently being or soon to be tested in clinical trials are emphasized. The results from these trials will provide important clues as to whether or not reactivating strategies could become significant components of a cure for HIV.

Lancet. 2013 Mar 28. pii: S0140-6736(13)60104-X. doi: 10.1016/S0140-6736(13)60104-X. [Epub ahead of print]

Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs.

Katlama C, Deeks SG, Autran B, Martinez-Picado J, van Lunzen J, Rouzioux C, Miller M, Vella S, Schmitz JE, Ahlers J, Richman DD, Sekaly RP.

Department of Infectious Diseases, Pierre and Marie Curie University, Pitié-Salpêtriere Hospital, Paris, France.

Abstract

Antiretroviral therapy for HIV infection needs lifelong access and strict adherence to regimens that are both expensive and associated with toxic effects. A curative intervention will be needed to fully stop the epidemic. The failure to eradicate HIV infection during long-term antiretroviral therapy shows the intrinsic stability of the viral genome in latently infected CD4T cells and other cells, and possibly a sustained low-level viral replication. Heterogeneity in latently infected cell populations and homoeostatic proliferation of infected cells might affect the dynamics of virus production and persistence. Despite potent antiretroviral therapy, chronic immune activation, inflammation, and immune dysfunction persist, and are likely to have important effects on the size and distribution of the viral reservoir. The inability of the immune system to recognise cells harbouring latent virus and to eliminate cells actively producing virus is the biggest challenge to finding a cure. We look at new approaches to unravelling the complex virus-host interactions that lead to persistent infection and latency, and discuss the rationale for combination of novel treatment strategies with available antiretroviral treatment options to cure HIV.

Clinical Pharmacology & Therapeutics (2013); 93 5, 382–384. doi:10.1038/clpt.2013.22

Commentaries

HIV Cure: Knocking on the Door

C M Durand1 and C Flexner1,2

1Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, Maryland, USA

2Division of Infectious Diseases, Department of Medicine, and Division of Clinical Pharmacology, Department of Pharmacology and Molecular Sciences and Department of International Health, Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, Maryland, USA

Abstract

Although major advances in drug development and public health are helping to control the HIV/AIDS epidemic, there is a strong rationale for pursuing a more definitive cure. Several bold but unproven strategies for HIV eradication are reviewed in this issue of CPT, including novel drugs, gene therapy, and bone marrow transplantation (BMT). Early results, including one probable case of HIV eradication in a leukemia patient, are intriguing but raise many questions.

Clinical Pharmacology & Therapeutics (2013); 93 1, 46–56. doi:10.1038/clpt.2012.202

State of the Art

Prospects for Treatment of Latent HIV

K M Barton1, B D Burch2, N Soriano-Sarabia2 and D M Margolis1,2,3

1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

2Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

3Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

Abstract

Recent advances in antiretroviral therapy (ART) have drastically improved the quality of life for people with HIV infection. However, owing to the persistence of latent HIV in the presence of therapy, patients must remain on therapy indefinitely. Currently, the solution to the HIV pandemic rests on the prevention of new infections and many decades of ART for the steadily expanding number of people infected worldwide. ART is costly, requires ongoing medical care, and can have side effects, thereby preventing its universal availability. Therefore, to escape the ironic burdens of therapy, efforts have begun to develop treatments for latent HIV infection. Current approaches propose either complete eradication of infection or induction of a state of stringent control over viral replication without ART. This review will discuss these strategies in detail and their potential for clinical development.

Comments

[Ole Sogaard]

I can only agree that part of the Telegraph story, and in particular its title was misleading. Unfortunately, as a consequence, the following coverage in the media has been blown out of proportion. To set things straight, "we are not on brink of an HIV cure" and I can say for sure that I never said or insuated that we were. Like many others, I believe that a cure for HIV is an achievable goal but that it most likely will take many years, numerous basic science discoveries as well as phase 1/2 trials before it may actually be reached.

[Richard Jefferys]

Thank you for your comment Dr. Søgaard. I recognize that the media often does poorly when it comes to science generally, and the headline and subhead of the Daily Telegraph article were the most outrageously erroneous elements. But there were many egregious aspects of the story itself.

I now see that those aspects have all been corrected, which is excellent news. But it is a shame they don't seem to have toned down the title. It is also unlikely, unfortunately, that readers misled by the original piece will subsequently see the revised version. A particular concern is causing potential research participants to pay less attention to the risks associated with these early trials due to gaining the false impression that participation will lead them to be cured of HIV infection.