Attacking latent HIV provirus: from mechanism to therapeutic strategies.

Abstract

The persistence of small population integrated proviral HIV genomes capable of expressing HIV within long-lived CD4 T cells is a fundamental obstacle to the eradication or cure of HIV infection. As potent antiretroviral therapy by itself appears to be an impractical approach to the eradication of this quiescent reservoir of HIV infection, new approaches are required. Initial studies failed to demonstrate that simultaneous, intensive antiretroviral therapy in combination with global inducers of CD4 T-cell activation could eradicate HIV infection. Global T-cell activation may induce viral replication and increase the number of susceptible uninfected target cells beyond the threshold that can be contained by current antiretroviral therapy. Future advances in antiretroviral therapy may, however, change this equation. An alternative approach to overcoming HIV latency is to develop agents capable of inducing the expression of quiescent HIV without enhancing de novo infection. More selective, targeted approaches may avoid the undesirable consequences of viral induction via signals that result in parallel T-cell activation. Such approaches using the cytokine IL 7, the novel protein kinase agonist prostratin, and inhibitors of the chromatin remodeling enzyme histone deacetylase have recently entered advanced preclinical and clinical testing. Many obstacles to the eradication of HIV infection exist. Encouraging advances in practical, targeted approaches to the major reservoir of persistence within resting CD4 T cells are, however, beginning to enter clinical testing.