HIV and the Church

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 impairment.

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,”[1] 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.

The 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.  

This 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.  

Another study presented at AIDS 2014 by Sharon Lewin, “Modeling the Effects of Vorinostat in vivo on Activation of Latent HIV Infection,”[2] 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 cure. 

The 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”[3], 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.

[1] Multidose Vorinostat 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.

[2] 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. 

[3] 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.