Targeting the Latent Reservoir for HIV-1

Abstract

Antiretroviral therapy can effectively block HIV-1 viral replication and prevent or reverse immunodeficiency in HIV-1-infected individuals. However, viral replication resumes within weeks of treatment interruption. The major barrier to cure is a small pool of resting memory CD4+ T cells that harbor latent HIV-1 proviruses. This latent reservoir is now the focus of an intense international research effort. We describe how the reservoir is established, challenges involved in eliminating it, and pharmacologic and immunologic strategies for targeting this reservoir. The development of a successful cure strategy will likely require understanding the mechanisms that maintain HIV-1 proviruses in a latent state and pathways that drive the proliferation of infected cells, which slows reservoir decay. In addition, cure will require the development of effective immunologic approaches to eliminating infected cells. There is renewed optimism about the prospect of a cure, and the interventions discussed here may pave the way.

Transcriptional Circuit Fragility Influences HIV Proviral Fate

“…Besides the possible fluctuations in activation of the viral phase (Tat function) previously observed (Weinberger et al, 2005), we argue the main component that must be taken into account during either of the proposed approaches to target the latent reservoir (Sengupta and Siliciano, 2018), is the level of activation of the host phase, which will set the threshold for activation of the cellautonomous viral phase.…”

“…Resting memory CD4 T cells harboring stably integrated HIV genomes are capable of producing infectious virus upon T cell activation. Two current approaches for targeting the latent HIV reservoir from patients include 'shock and kill' (to reactivate all latent viruses and eliminate the cells containing induced virus through immune surveillance mechanisms) and 'block and lock' (to devise strategies for long-term, durable slicing of latent proviruses) (Sengupta and Siliciano, 2018). Even within one patient, the number of latent reservoirs and proviruses harboring replication-competent proviruses is immense and can lead to clonal expansion over time (Ho et al, 2013;Maldarelli et al, 2014;Wang et al, 2018).…”

Antigen responsive CD4+T cell clones contribute to the HIV-1 latent reservoir

“…A number of ideas have been proposed to explain HIV-1 persistence. These include low-level ongoing HIV-1 replication in sanctuary sites where drug concentrations are insufficient to block virus replication (Lorenzo-Redondo et al, 2016), and infected T cell longevity (Hatano et al, 2013;Sengupta and Siliciano, 2018). Cell division was not initially considered as a mechanism of proviral persistence because the signals that induce T cell division, such as NF-κB, also tend to reactivate latent proviruses and might lead to cell death (Siliciano and Greene, 2011).…”

Quadruplex qPCR for qualitative and quantitative analysis of the HIV-1 latent reservoir

“…Longitudinal studies performed on individuals on cART indicate that the latent reservoir has a half-life of 44 months (Chun et al, 1999;Siliciano et al, 2003). Thus, treatment interruption leads almost invariably to rapid viral rebound and therapy with cART is required for the lifetime of the infected individual (Margolis and Archin, 2017;Sengupta and Siliciano, 2018).…”

“…The evaluation of HIV-1 curative strategies requires sensitive, specific and precise assays to quantify and characterize the latent HIV-1 reservoir. Yet, to date most approaches show major discrepancies in infected cell frequencies (Eriksson et al, 2013;Sengupta and Siliciano, 2018). These inconsistencies constrain the accurate assessment of HIV-1 cure efforts and could obscure a meaningful intervention (Henrich et al, 2017;Sengupta and Siliciano, 2018).…”