AIDS Therapy

"Understanding the mechanism of latency is critical for determining whether this reservoir can be eliminated... . There is interest in strategies that 'flush' cells out of latency. Interleukin-2 and antibodies to CD3 induce T-cell activation in vivo. However, initial studies in patients have shown significant toxicities and no meaningful decay of the latent reservoir. An ideal agent would induce expression of latent HIV without inducing global T-cell activation. However, this is a tall order given that HIV-1 gene expression is so intimately linked to T-cell activation. Recently, two groups have demonstrated that a naturally occurring, non-tumor-promoting phorbol ester, prostratin, induces the expression of latent HIV-1 in resting CD4 T cells without inducing cellular proliferation or enhancing de novo HIV-1 infection. Even if this strategy proves successful, there remains the possibility that other stable reservoirs exist, each of which would have to be dealt with in a cell type-specific fashion."

In summary, HIV-1 latency represents a formidable therapeutic challenge for which there are no easy answers. As a result of viral tropism for activated CD4+ T cells and the reversion of some of these cells to a profoundly quiescent and long-lived memory state, the virus can persist through the same mechanisms responsible for the most fundamental characteristic of the immune system, immunologic memory. The dependence of viral gene expression on host factors that are inactive in resting T cells means that viral gene expression can be largely or completely extinguished in latently infected cells. In the absence of virus gene expression, latently infected cells will differ from their uninfected counterparts by only the presence of 10 kb of viral DNA integrated into a host cell chromosome. In this case, the virus is persisting as genetic information in a stably integrated form in rare memory cells that cannot be distinguished from their uninfected counterparts. It is difficult to envision any targeting mechanism that will allow specific elimination of this reservoir. Optimism stems from the fact that antiretroviral drugs come very close to stopping the active replication of the virus, with its attendant damage to the immune system. In some patients on HAART, the evolution of drug- resistant viruses, which is the principal cause of treatment failure, is largely halted. The development of nontoxic, convenient, and affordable combinations of antiretroviral drugs may allow infected individuals to live a normal life despite the indefinite persistence of latent HIV-1 in resting memory CD4+ T cells.