Human immunodeficiency virus (HIV) latency: the major hurdle in HIV eradication

Abstract

Failure of highly active antiretroviral therapy to eradicate the human immunodeficiency virus (HIV), even in patients who suppress the virus to undetectable levels for many years, underscores the problems associated with fighting this infection. The existence of persistent infection in certain cellular and anatomical reservoirs appears to be the major hurdle in HIV eradication. The development of therapeutic interventions that eliminate or limit the latent viral pools or prevent the reemergence of the viruses from producing cells will therefore be required to enhance the effectiveness of current antiretroviral strategies. To achieve this goal, there is a pressing need to understand HIV latency at the molecular level to design novel and improved therapies to either eradicate HIV or find a functional cure in which patients could maintain a manageable viral pool without AIDS in the absence of antiretroviral therapy. The integrated proviral genome remains transcriptionally silent for a long period in certain subsets of T cells. This ability to infect cells latently helps HIV to establish a persistent infection despite strong humoral and cellular immune responses against the viral proteins. The main purpose of this report is to provide a general overview of the HIV latency. We will describe the hurdles being faced in eradicating latent HIV proviruses. We will also briefly discuss the ongoing strategies aimed toward curing HIV infection.

Figure 1

Factors regulating HIV provirus into latency. Lack of transcription factors in resting CD4⁺ T cells along with repressive chromatin structures impede the HIV transcriptional initiation rate, which in turn translates into reduced Tat levels that ultimately yield the entry of provirus into latency. After cell activation, the level of transcriptional factors rises and resultant Tat production reinstates HIV transcription. See details in the text.

Figure 2

A schematic representation of turnover of latently infected T cells. Naive T cells get activated after antigenic stimulation and become susceptible to HIV infection. Most of infected cells die, but a minute fraction turns into Tcm for the encountered antigen. Antigenic stimulation of Tcm results in their activation and conversion into Tem. Their metabolically active state leads to the reactivation of integrated latent provirus that eventually contributes to the blips and viremia. Most of the T cells die off because of viral production toxicity and clearing the antigens from the system, but a tiny fraction gets differentiated into Tcm specific for that antigen and replenishes the source. HIV homeostatic proliferation induced by IL-7 and IL-15 results in Tcm differentiation into partially activated Ttm, which support partial reactivation of latent HIV. Some of Ttm revert to Tcm. See details in the text.