Could a New Combination Treatment Strategy Eradicate HIV?

A new combination strategy could improve HIV treatment by destroying virus circulating in the body as well as HIV hiding in CD4 T-cells, according to a study published in the June 21, 2009 advance online issue of Nature Medicine

The authors suggested that eradication of HIV might be achieved by combining currently available antiretroviral drugs that target viral replication with therapies that interfere with T-cell persistence and proliferation.

Even when highly active antiretroviral therapy (HAART) fully suppresses HIV replication in the blood, the virus persists in a reservoir of latently infected CD4 T-cells. In order to fully eradicate HIV, it would be necessary to both halt replication of circulating virus and disable HIV within latent cells (which may require destroying the cells themselves).

In the current study, the investigators identified 2 types of long-lived immune cells -- central memory and transitional memory CD4 T-cells -- as the major cellular reservoirs of HIV. Furthermore, they determined that 2 different mechanisms ensure viral persistence.

Proviral DNA, or HIV genetic material, is integrated into the chromosomes of these memory T-cells; as the cells divide and proliferate, the "daughter" cells also contain HIV DNA that can trigger new virus production.

Among individuals who experience good CD4 cell reconstitution after starting HAART, the researchers found that HIV primarily persisted in central memory T-cells -- long-lived cells that "remember" how to respond to specific pathogens encountered in the past. This viral reservoir is maintained through long cell survival and low-level antigen-driven proliferation, but eventually the virus is slowly depleted over time.

In contrast, proviral DNA was mainly detected in transitional memory cells in individuals with undetectable plasma viral load, low CD4 cell counts, and more extensive interleukin-7-mediated homeostatic proliferation (cell proliferation stimulated by cytokines).

These findings, the researchers said, suggest that it may be possible to achieve HIV eradication by combining therapies (including current antiretroviral drugs) that inhibit viral replication, plus "intelligent targeted chemotherapy" (like some cancer drugs) that interferes with persistence and proliferation of memory T-cells containing hidden virus.

Université de Montréal, Montréal, Québec, Canada; Royal Victoria Hospital, McGill University Health Centre, McGill University, Montréal, Québec, Canada; National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; University of Minnesota, Minneapolis, MN; Oregon Health and Science University, Portland, OR; Vaccine and Gene Therapy Institute, Port-Ste Lucy, FL.

7/07/09

Reference

N Chomont, M El-Far, P Ancuta, and others. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation (Abstract). Nature Medicine. June 21, 2009 [Epub ahead of print].