Establishment and maintenance of HIV latency: model systems and opportunities for intervention

Abstract

HAART has succeeded in reducing morbidity and mortality rates in patients infected with HIV. However, a small amount of replication-competent HIV can persist during HAART, allowing the virus to re-emerge if therapy is ceased. One significant source of this persistent virus is a pool of long-lived, latently infected CD4(+) T cells. This article outlines what is known about how this reservoir is established and maintained, and describes the model systems that have provided insights into the molecular mechanisms governing HIV latency. The therapeutic approaches for eliminating latent cells that have been attempted are also discussed, including how improvements in understanding of these persistent HIV reservoirs are being used to develop enhanced methods for their depletion.

Figure 1. Potential methods for the activation of latent virus and subsequent killing of infected cells

A wide range of molecules are capable of inducing expression of HIV from a latent provirus. Some of these (such as anti-CD3⁺ anti-CD28 costimulation) lead to powerful activation of both the host cell and the latent provirus, whereas others (e.g., treatment with prostratin or IL-7) can activate latent HIV expression without inducing significant stimulation and proliferation of the host cell. After stimulation, the latent provirus continues with the latter part of the virus lifecycle, resulting in expression of viral proteins and production of new virions. Once it has begun expressing viral proteins, the host cell is susceptible to viral cytopathic effects and immune effector mechanisms (such as killing by cytotoxic T cells). Anti-HIV Env immunotoxins can specifically bind to and kill cells expressing HIV Env proteins; therefore, they may prove useful in purging strategies in conjunction with latency activators. Throughout this process, virus spread is prevented by the presence of HAART. HDAC: Histone deacetylase.