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Developing tools to attack persistent HIV infection

Now fully twenty five years after the beginning of the AIDS pandemic, enormous gaps in knowledge limit both prevention and treatment. Understanding human immunodeficiency (HIV) transmission has been difficult in the absence of identifying large numbers of transmission events and collecting specimens in the first days and weeks of infection.

In order to fill some of the critical gaps in knowledge, the US National Institutes of Health (NIH) has awarded a large grant to a group of investigators to implement The Center for HIV/AIDS Vaccine Immunology (CHAVI), as a US Government contribution to the Global HIV-1 Enterprise. CHAVI investigators will use state-of-the art technology through carefully designed, focused, and coordinated studies to address Enterprise-identified gaps in our knowledge targeted at enabling the production of a successful HIV-1 vaccine. To do this CHAVI will work to discover new information about acute HIV-1 infection, the correlates of protective immunity to HIV-1, and the development of novel methods of inducing protective immunity at mucosal sites.

In part to identify patients in whom acute HIV infection can be studies, and in part as a general public health strategy, North Carolina has been implemented a program to detect subjects with acute HIV in the first month (in some even the first weeks) of infection. Detection of subjects with acute HIV infection is accomplished by using a novel and inexpensive RNA pooling strategy for detection of acute infection. Patients in whom acute infection is detected are offered enrollment into our studies, which include intensive investigation of the immune response, and the implementation of immediate antiviral therapy (known as HAART).

However, 10 years after the definition of effective HAART, no one with HIV infection has been cured. Current HAART can nearly eliminate viremia in patients with HIV infection. However, despite antiretroviral therapy, a small population long-lived CD4+ T cells remains persistently infected and unrecognized by the immune system, with minimal expression of HIV genes or proteins. The persistence of quiescent HIV infection is a major obstacle to eradication and cure of HIV infection. New therapeutic approaches to this quiescent or latent state of HIV infection are needed.

One approach to overcome HIV latency is to develop agents capable of inducing expression of quiescent HIV without enhancing de novo infection, so that persistent viral infection could be cleared. Our recent studies suggest a clinically practical approach to upregulate HIV gene expression in latently infected cells without inducing global cell activation. We have found that the chromatin remodeling enzyme histone deacetylase 1 (HDAC1) plays a critical role in HIV latency. A clinically available HDAC inhibitor, valproic acid (VPA), induces outgrowth of latent HIV ex vivo without T cell activation or increased de novo HIV infection. In a pilot clinical experiment, we found significant depletion of replication-competent HIV within the resting CD4+ T cell compartment in 3 of 4 volunteers given intensified HAART and VPA.

We are now combining studies acute HIV infection and early treatment of acute infection with those that aim to disrupt latent HIV infection. Ultimately, it is hoped that cure of infection will be accomplished through use of valproic acid and other agents which prevent HIV latency, in combination with brief but aggressive antiretroviral therapy at this earliest possible moment of HIV infection. An iterative program will analyze progress towards eradication, and develop further agents for clinical testing. We will deliver candidate curative treatments to study subjects identified during the first weeks of antibody-negative acute HIV infection, attempting to eliminate the latent reservoir before it is fully established. In this way, we will create optimal conditions for a first demonstration of curative HIV therapy. Once this can be accomplished in the setting of acute infection, it may establish the basis of eradication of chronic HIV infection as well. Simultaneously, studies of the immune response in acute infection in these study volunteers may identify protective immune responses that are lost, thereby defining new goals for the development of protective vaccines.

http://www.sph.unc.edu/research/spotlight_on_david_margolis_md_3032_3122.html

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