How does the timing of antiretroviral therapy initiation in acute infection affect HIV reservoirs?

Abstract

Purpose of review: The long-lived viral reservoir is a major obstacle to achieving a cure for HIV. Therapeutic strategies, such as early antiretroviral therapy (ART), may be a prerequisite to achieving long-term control of viral replication upon ART withdrawal.

Recent findings: HIV persistence is established early in acute HIV infection (AHI) with infection in long-lived memory CD4⁺ T cells. Studies conducted in nonhuman primates have suggested that this could occur as early as 3 days postinfection; however, the timing in humans is uncertain. ART during AHI significantly restricts the HIV reservoirs as compared with later treatment. Early ART, particularly prior to the detection of HIV immunoglobulin M, may also reduce the contribution of the long-lived central memory CD4⁺ T cells to the total HIV reservoir, a profile observed in individuals who naturally control HIV without ART.

Summary: It is clear that early ART has a greater impact in limiting the HIV reservoirs than later treatment. However, latently infected long-lived memory CD4⁺ T cells persist in most early treated individuals. Therefore, additional interventions will likely be required to eliminate all cells capable of producing replication-competent virus but treatment in AHI may be the critical first step in containing the HIV reservoirs.

FIGURE 1

The size and composition of the latent HIV reservoir is affected by early ART. (a) Subsets of CD4 T cells can be identified based on the levels of expression of several cellular markers including CD45RA, CCR7, CD27 and CD95. The pathway of T cell differentiation, that is, the sequence of development of the different T-cell subsets, remains elusive in humans, and it is unclear if the differentiation pathway is linear or branched, one-way or reversible [31]. (b) In chronically infected patients, the contribution of TCM cells to the overall pool of infected cells is important [30]. As these cells are long lived, they survive after years of ART and represent the major latent HIV reservoir in patients who started ART during chronic infection [24^■]. The contribution of T_SCM cells also increases with time [27^■■]. Patients with acute or recent infection display a small size of the reservoir (as depicted by a reduced size of the grey box). In addition, their T_CM cells may be relatively preserved from infection, with a greater contribution of short-lived cells. After years of ART, this may result in a reservoir of a very small magnitude. ART, antiretroviral therapy.