Researchers identify promising agents for HIV cure research

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Researchers from the University of North Carolina and Merck are identifying promising new leads in the search for agents that may be able to purge HIV from resting CD4 cells, a key requirement for any prospect of a cure for HIV infection.

The findings, reported by David Margolis and Nancie Archin in the September 15th edition of AIDS, show that a group of compounds called class 1 HDAC inhibitors show the most promise in activating previously latent HIV within resting CD4 cells. The findings may also explain why previous studies using another HDAC inhibitor, the antiepileptic valproic acid, showed only weak effect.

After integration into the host genome HIV can remain silent within a resting CD4 cell for many years, provided that it is not stimulated into replication by signals that hit the long terminal repeat portion of the virus’s genetic code. Once stimulation occurs, a complex chain of events occurs within the cell that leads to HIV replication.



The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.


The ‘HIV reservoir’ is a group of cells that are infected with HIV but have not produced new HIV (latent stage of infection) for many months or years. Latent HIV reservoirs are established during the earliest stage of HIV infection. Although antiretroviral therapy can reduce the level of HIV in the blood to an undetectable level, latent reservoirs of HIV continue to survive (a phenomenon called residual inflammation). Latently infected cells may be reawakened to begin actively reproducing HIV virions if antiretroviral therapy is stopped. 

CD4 cells

The primary white blood cells of the immune system, which signal to other immune system cells how and when to fight infections. HIV preferentially infects and destroys CD4 cells, which are also known as CD4+ T cells or T helper cells.




A disease in which the skin develops raised, rough, reddened areas.

Researchers interested in curing HIV believe that the only way to do it is by purging the body of all reservoirs of latent virus, since even very small quantities of latent virus would provide enough material for an eventual resurgence of viral load to pre-treatment levels if antiretroviral therapy is removed. The only way the reservoir could be purged, according to current thinking, is by activating latent virus while giving antiretroviral treatment in order to prevent further rounds of infection.

The general consensus among researchers is that large-scale activation of latent HIV would not lead to loss of viral control, because current therapies are highly efficient at suppressing viral load, and also because the size of the reservoir of infected cells is modest in comparison to the size of the virus population prior to treatment.

However, finding ways to purge the viral reservoir will not be easy. HDAC (histone deacetylase) inhibitors have been proposed as one means; they are expected to work by inhibiting the cellular mechanism – histone deacetylation - exploited by HIV to remain silent. Previous attempts using valproic acid have not been successful, leading some to argue that the approach is flawed.

In their experiments the University of North Carolina group took a variety of HDAC inhibitors and tested their ability to summon up HIV replication from resting CD4 cells gathered from people with undetectable viral load on antiretroviral treatment.

They found that not all HDAC inhibitors stimulated viral replication to the same extent, and in particular they determined that inhibitors which target the class 1 HDAC of types 1, 2 , 3 and which also targeted the class 2 HDAC type 6 may be particularly efficient.

The findings are likely to lead to new interest in identifying HDAC inhibitors targeting these specific HDACs, and in identifying the mechanisms involved in HDAC inhibition at each of the specific sites affected by the most promising compounds.

Part of this quest will focus on identifying compounds that interfere as little as possible with other cellular processes, in order to limit toxicity. Human studies of HDAC inhibitors in HIV infection may prove next to impossible if the toxicities are substantial or poorly understood, given the relatively well-tolerated antiretroviral regimens now available.

More specific HDAC inhibitors are already in use or in development as cancer therapies, and are also being investigated for use in Alzheimer’s disease, Huntington’s disease, psoriasis and fungal infections, and work in these areas is likely to benefit HIV research.

Archin NM et al. Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors. AIDS 23: 1799-1806, 2009.