HIV-1 Reservoirs During Suppressive Therapy

Abstract

The introduction of antiretroviral therapy (ART) 20 years ago has dramatically reduced morbidity and mortality associated with HIV-1. Initially there was hope that ART would be curative, but it quickly became clear that even though ART was able to restore CD4(+) T cell counts and suppress viral loads below levels of detection, discontinuation of treatment resulted in a rapid rebound of infection. This is due to persistence of a small reservoir of latently infected cells with a long half-life, which necessitates life-long ART. Over the past few years, significant progress has been made in defining and characterizing the latent reservoir of HIV-1, and here we review how understanding the latent reservoir during suppressive therapy will lead to significant advances in curative approaches for HIV-1.

Keywords: HIV-1; HIV-1 reservoirs; latent HIV-1; long-term ART; memory CD4(+) T cells; persistent HIV-1.

Figure 1. Latent HIV Is a Multifactorial Challenge

In addition to the CD4⁺ memory T cell subsets found in the peripheral blood, the lymphoid tissue, gut-associated lymphoid tissue, and the central nervous system are significant anatomical focuses of latent HIV infection. Furthermore, additional tissues such as the lungs and skin may also contain cells harbouring latent HIV. Additionally, unknown potential reservoirs remain to be defined. Each of these tissues contains unique cell types that contribute to the persistence of HIV during effective ART. T_H – CD4+ helper T cells, NK – natural killer cells.

Figure 2. Latent HIV Reservoir Is Maintained Through Cell Proliferation

CD4⁺ memory T cells undergo cellular proliferation through two mechanisms that can be detected individually. The first is due to specific antigenic stimulation by antigen presenting cells (APC), which results in a large expansion of a single cell. Second, the overall population of memory T cells is kept at a relatively constant number through homeostatic proliferation. When the total numbers of memory T cells decline, the remaining cells are stimulated to proliferate by cytokines such as interleukin-7 (IL-7). If these cells contain latent HIV, it is also expanded, which increases the size of the latent reservoir. As the latent reservoir is stable over time, it is likely that decline of virus due to cell death is somewhat balanced with proliferation.