April 12, 2013
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 that addresses the article and clarifies the views of his research group. [Click here to see the original blog post, which contains Dr Sogaard's comment at the bottom of the page.]
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."
Abstracts With Links
Hum Vaccin Immunother. 2013 Apr 1;9(4). [Epub ahead of print]
Eliminating the latent HIV reservoir by reactivation strategies: Advancing to clinical trials.
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.
Clinical Pharmacology & Therapeutics (2013); 93 5, 382-384. doi:10.1038/clpt.2013.22
HIV Cure: Knocking on the Door
Clinical Pharmacology & Therapeutics (2013); 93 1, 46-56. doi:10.1038/clpt.2012.202
Prospects for Treatment of Latent HIV
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.