Predicting Post-treatment HIV Remission: Does Size of the Viral Reservoir Matter?

Abstract

Combination antiretroviral therapy (ART) suppresses human immunodeficiency virus (HIV) replication and improves immune function. However, due to the persistence of long-lived HIV reservoirs, therapy interruption almost inevitably leads to a fast viral rebound. A small percentage of individuals who are able to control HIV replication for extended periods after therapy interruption are of particular interest because they may represent a model of long-term HIV remission without ART. These individuals are characterized by a limited viral reservoir and low reservoir measures can predict post-treatment HIV remission. However, most individuals with a low reservoir still experience fast viral rebound. In this Perspective, we discuss the possible reasons behind this and propose to develop an integral profile, composed of viral and host biomarkers, that could allow the accurate prediction of post-treatment HIV remission. We also propose to incorporate information on the chromatin context of the proviral integration sites into the characterization of the HIV reservoir, as this likely influences the reactivation capacity of latent proviruses and, together with the actual number of intact proviruses, contributes to the replication competence of the reservoir.

The Splice of Life: Does RNA Processing Have a Role in HIV-1 Persistence?

“…HIV-1 forms long-lived reservoirs in infected individuals, which persist despite decades of suppressive ART and fuel viral rebound if therapy is interrupted. The persistence of viral reservoirs is the main obstacle to achieving an HIV-1 cure [ 2 , 3 , 4 , 5 ]. Latent infection of resting CD4+ T cells and possibly some other cell types, such as macrophages, is thought to be the main mechanism of HIV-1 persistence in peripheral blood and lymphatic tissues [ 6 , 7 ].…”

Assessing proviral competence: current approaches to evaluate HIV-1 persistence

“…These results suggest that the chromatin context of the provirus and its integration site-imposed reactivation potential could be as important for the replication competence as the genetic intactness [86], and provide a possible explanation why only a tiny fraction of intact proviruses can be reactivated ex vivo. The intact provirus frequency should thus be considered the upper limit of the replication-competent reservoir size [26,27].…”

“…Because the success of HIV-1 cure efforts demands sensitive, precise, and cost-effective methods to assess HIV-1 persistence among the participants of clinical trials and in large cohort studies, a number of novel angles to approach the measurement of viral persistence and reservoirs have arisen in the recent years (reviewed in [9,[21][22][23][24][25][26][27]). Here, we provide an update on recently developed methods that allow a better estimation of the viral reservoir size and a more thorough characterization of HIV-1 persistence.…”

Towards a molecular profile of antiretroviral therapy-free HIV remission

“…Since the first description of PTC, many research efforts were undertaken to elucidate its underlying factors and critical parameters. Several excellent reviews have summarized the findings on PTC and virological remission [31][32][33][34][35][36].…”

“…Since the first description of PTC, many research efforts were undertaken to elucidate its underlying factors and critical parameters. Several excellent reviews have summarized the findings on PTC and virological remission [31–36]. Here, we aim to discuss the latest findings on proposed predictive factors for these phenomena and to highlight the need for the development of a molecular profile that could reliably predict ART-free HIV remission…”