Written by: Jeannie Wraight, Mariel Selbovitz, MPH and David Miller
In the search for a cure, Vorinostat yields are less than expected in Melbourne
Currently HIV-infection can be controlled through the use of
antiretroviral therapy (ART). By correctly taking a combination of
antiretroviral drugs, the HIV viral load (the amount of virus in the blood) can
be reduced to below the level of detection.
This allows the immune system to regain control and
effectively defeat many other pathogens (germs, viruses, bacteria and
parasites) that enter the body, promoting the health of HIV patients.
Despite the benefit obtained by ART, low-level ongoing
replication of HIV continues to occur. As a reaction to this continuous
replication, the immune system is in a constant state of activation in an
attempt to control infection. This is called inflammation. It is believed that
inflammation is a major contributor to many non-AIDS related conditions such as
cardiovascular disease, some cancers, liver and kidney disease and cognitive
HIV reservoirs exist throughout the body that harbor HIV in
resting cells. These cells are inactive and as such cannot be killed by ART. It
is thought that these reservoirs contribute to inflammation. It is also thought
necessary to rid the body of these latently infected cells in order to “cure”
or eradicate HIV.
“Shock and kill” is one of the most heavily invested in
strategies to “cure” HIV. A great deal
of time and research funds have been directed towards finding a way to activate
and kill off latent HIV. On the HIV
eradication front, the Towards an HIV Cure two-day symposium that started at
AIDS 2012 in Washington, D.C. took place immediately preceding the opening of
AIDS 2014. Containing some of the most
important presentations of the conference, the gathering’s attendance is
limited to 200 people or by invitation.
The symposium was co-chaired by Francoise Barre-Sinoussi, IAS President
and 2008 Nobel laureate (for her discovery of HIV as the virus that causes AIDS),
Steven Deeks, Professor of Medicine at the University of California, San
Francisco, and Sharon Lewin, Director of the Infectious Disease Unit at Alfred
Hospital, Monash University.
Presentations addressing latently infected cells included: “Epigenetic
Regulation of HIV Latency;” “A New Family of Compounds That Reactivate Latent
HIV in Central Memory T-Cells;” “Induction and Clearance of Latent HIV
Infection: Modeling Viral Clearance by Immune Effectors Using Cells from
ART-treated Patients;” and “The HDAC Inhibitor Romidepsin is Safe and
Effectively Reverses HIV Latency in Vivo.”
Regrettably, only the fortunate 200 attendees and invited speakers are
privy to the information from the meeting as there was no reporting or
information publicly available beyond the program.
One of the most researched approaches to “waking up” these resting
cells is the use of HDAC inhibitors. Histone deacetylase inhibitors (HDAC inhibitors)
are used in psychiatry, neurology and
cancer. These drugs are also being studied for treatment in parasitic and
inflammatory diseases. Several HDAC
inhibitors, such as vorinostat, have been used in an
attempt to activate latent HIV in reservoirs.
HDAC inhibitors activate HIV transcription in latently infected T-cells
in HIV patients on suppressive ART and have also been reported to have
widespread, largely suppressive effects on both innate and adaptive immune
responses. A study of vorinostat was described in an
abstract presented at AIDS 2014.
In a study led by Sharon Lewin, “Multidose Vorinostat in HIV-infected
Individuals on Effective ART Leads to an Increase in Regulatory T-Cells but No
Change in Indicible Virus or HIV-specific T Cells,” vorinostat was given to 20 people with HIV on ART for 14 days to
see if the drug led to activation of latent cells and/or adaptive immune
response (B and T-cell response, mediated by immunological memory).
In this study 90% of participants
experienced a significant increase in HIV production from latently infected
cells. Viral load remained undetectable for all but two participants. There were no significant changes in the proportion of
HIV-infected cells in the blood.
administration of vorinostat to HIV infected individuals on ART also led to
significant potentially adverse immunological changes, including an increase in
regulatory T-cells without any significant change in HIV-specific T cells.
study shows that vorinostat
did activate a portion of latently infected cells. However, more studies will
be needed to determine exactly what that means. It is unknown what percentage
of the reservoir was activated or what happens to these cells after they are
activated. The authors concluded that
future strategies to reduce the latent reservoir will require more potent
latency reversing agents, likely in combination with immune modulators that
boost HIV-specific immunity.
study presented at AIDS 2014 by Sharon Lewin, “Modeling the Effects of
Vorinostat in vivo on Activation of Latent HIV Infection,”
complemented the previous study by constructing a mathematical model that could
accurately fit the change in cell-associated unspliced HIV RNA. The authors developed two viral dynamic
models that included latently infected cells and the effects of vorinostat treatment. The model that included two latently infected
cell populations, one that was reactivated within one day of treatment and one
that was slowly reactivated upon treatment, fit the data better than the model
with only one latently infected cell population. The model suggested that treatment with vorinostat
in conjunction with antiretroviral therapy may also reduce the size of the
latent reservoir, which is touted to be the major barrier to achieving a
central nervous system (CNS) is an important reservoir in HIV that is sensitive
to the neurotoxic effects of HIV and antiretroviral therapy. In the abstract “Preliminary Assessment of
the Neurocognitive Effects of Vorinostat Administration in HIV Eradication”,
David Margolis and colleagues from the University of North Carolina at Chapel
Hill looked at neurocognitive functioning in patients receiving vorinostat. Five patients received 400 mg of vorinostat
daily Monday-Wednesday for four weeks, followed by another four week cycle
after a five-six week rest period.
Neurocognitive functioning was assessed at the beginning and the end of
the study in the areas of language, motor, learning, memory, speed of
processing, attention/working memory and executive functioning. No significant change in neurocognitive
performance was found, initially indicating vorinostat is safe for the
CNS. However, with the dosing schema
used, repeated and potent induction of viral expression was not seen, limiting
the relevance of this study’s results.
in HIV-infected individuals on effective ART leads to an increase in regulatory
T cells but no change in inducible virus or HIV-specific T cells. Wightman, J.H.
Elliot, A.E. Solomon, R. Fromentin, F.A. Procopio, J. Zeidan, T. Spelman, N.
Chomont, P.U. Cameron, R.P. Sekaly, S.R. Lewin.
AIDS 2014, Melbourne, Australia, July 2014, LBPE07.
Modeling the effects of vorinostat in vivo on activation of latent HIV
infection. S. Lewin, K. Ruian, J. Elliott, A. Perelson. AIDS 2014, Melbourne,
Australia, July 2014, THPE017.
Preliminary assessment of the neurocognitive effects of vorinostat
administration in HIV eradication. K. Robertson, J. Kuruc, N. Archin, J. Eron,
D. Margolis. AIDS 2014, Melbourne, Australia, July 2014, WEPE018.