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.
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