The Latent Reservoir for HIV-1: How Immunologic Memory and Clonal Expansion Contribute to HIV-1 Persistence

Abstract

Combination antiretroviral therapy (ART) for HIV-1 infection reduces plasma virus levels to below the limit of detection of clinical assays. However, even with prolonged suppression of viral replication with ART, viremia rebounds rapidly after treatment interruption. Thus ART is not curative. The principal barrier to cure is a remarkably stable reservoir of latent HIV-1 in resting memory CD4+ T cells. Here we consider explanations for the remarkable stability of the latent reservoir. Stability does not appear to reflect replenishment from new infection events but rather normal physiologic processes that provide for immunologic memory. Of particular importance are proliferative processes that drive clonal expansion of infected cells. Recent evidence suggests that in some infected cells, proliferation is a consequence of proviral integration into host genes associated with cell growth. Efforts to cure HIV-1 infection by targeting the latent reservoir may need to consider the potential of latently infected cells to proliferate.

Use of broadly neutralizing antibodies for HIV‐1 prevention

“…As the virus replicates, both arms of the adaptive immune response are stimulated to generate T cells and antibodies, but these fail to clear HIV-1, since the infected cell population is well established in tissues (19, 20), likely within a few days of exposure (based on primate model data), and prior to the development of immunity. HIV-1 infection is further aided by the rapid appearance of viral variants over time, termed the quasispecies (21).…”

Immunosenescence and hurdles in the clinical management of older HIV-patients

“…43 Memory T cells can be divided into 2 main subsets, central memory (TCM; cells with high levels of CD62L and CCR7) and effector memory cells (TEM; cells with low levels of CD62L and CCR7, which actively expresses effector functions and traffics to peripheral rather than secondary lymphoid tissues), based on expression of homing and chemokine receptors involved in preferential trafficking to secondary lymphoid organs or peripheral sites, respectively. 43,44 Several models of memory T-cell generation have been proposed, including the hypothesis that memory T-cells rapidly distinguish themselves from conventional effector T-cells during the primary immune response. Most data support the model of na€ ıve T-cells differentiating into effector T-cells, then further differentiating into memory T-cells.…”

Loss of immune homeostasis dictates SHIV rebound after stem-cell transplantation

“…Strategies designed to eradicate or induce durable remission of latent HIV-1 infection face 2 major challenges: virus-infected immune cells, chiefly CD4 + T cells, must be destroyed, while broader innate and adaptive immune defenses must be retained (1,2). The success of hematopoietic stem cell transplantation in eradicating HIV-1 in the Berlin patient highlights the importance of this intervention, as it remains the only HIV-1 functional cure described to date (3,4).…”