No evidence of ongoing HIV replication or compartmentalization in tissues during combination antiretroviral therapy: Implications for HIV eradication

Abstract

HIV persistence during combination antiretroviral therapy (cART) is the principal obstacle to cure. Mechanisms responsible for persistence remain uncertain; infections may be maintained by persistence and clonal expansion of infected cells or by ongoing replication in anatomic locations with poor antiretroviral penetration. These mechanisms require different strategies for eradication, and determining their contributions to HIV persistence is essential. We used phylogenetic approaches to investigate, at the DNA level, HIV populations in blood, lymphoid, and other infected tissues obtained at colonoscopy or autopsy in individuals who were on cART for 8 to 16 years. We found no evidence of ongoing replication or compartmentalization of HIV; we did detect clonal expansion of infected cells that were present before cART. Long-term persistence, and not ongoing replication, is primarily responsible for maintaining HIV. HIV-infected cells present when cART is initiated represent the only identifiable source of persistence and is the appropriate focus for eradication.

New Frontiers in Measuring and Characterizing the HIV Reservoir

“…Whether these particles are able to establish new infections under suppressive ART is a historical area of debate (Shen and Siliciano, 2008;Lorenzo-Redondo et al, 2016;Margolis et al, 2016;Martinez-Picado and Deeks, 2016); however, the overwhelming majority of evidence supports the notion that active viral replication does not occur during suppressive therapy. Rather, (1) long-lived cells infected prior to ART-initiation and (2) expansion of infected cells through cell division during suppressive therapy are responsible for persistence of the reservoir on long-term suppressive ART (Maldarelli, 2015;Bui et al, 2017;Kearney et al, 2017;Anderson and Maldarelli, 2018;Mok et al, 2018;Wang et al, 2018a;Bozzi et al, 2019). Nonetheless, upon cessation of suppressive ART, there is a rebound of viremia from the reservoir on the timescale of weeks and in general, progression of HIV disease if ART is not resumed (Chun et al, 1999;Hamlyn et al, 2012).…”

The forces driving clonal expansion of the HIV-1 latent reservoir

“…Indeed, early HIV-1-infection (within 4 weeks of expansion) can persist as clonally expanded HIV-1-infected cells [8]. However, it is the HIV-1-infected cells which are archived immediately before ART (which are likely survivors of ongoing immune selection pressure), as opposed to the initial peak viremia clones, which persist and undergo clonal expansion after years of ART [9,10]. The persistence of HIV-1-infected cells does not mean that the same HIV-1-infected cells remain unchanged over the course of ART.…”

“…However, three independent studies demonstrated that~56% of cells harboring replicationcompetent HIV-1 proviruses undergo clonal expansion [17][18][19]. Similarly, HIV-1-infected cells in the lymphoid tissue undergo clonal expansion with no new rounds of ongoing replication under suppressive ART, as evidenced by the lack of phylogenetic evolution [10,20,21]. Considering that these observations are likely affected by under sampling (many clones are not large enough to be detected as expanded), these studies suggest that the majority of the latent reservoir are likely maintained by clonal expansion [17][18][19]22].…”

Measuring the Success of HIV-1 Cure Strategies

“…On the other hand, the contribution of low-level virus replication in anatomical compartments with sub-optimal drug concentrations, such as lymph nodes (LN), to LR maintenance is a topic of continued debate (Fletcher et al, 2014;Fukazawa et al, 2015;Lorenzo-Redondo et al, 2016;Nolan et al, 2017;Bozzi et al, 2019). Generally, most studies demonstrate little evidence of provirus evolution in ART suppressed patients, refuting the likelihood that ongoing replication is continually seeding the reservoir (Bailey et al, 2006;Chomont et al, 2009;Josefsson et al, 2013;Hiener et al, 2017;Lee et al, 2017;Van Zyl et al, 2017;Bozzi et al, 2019;De Scheerder et al, 2019). Additionally, ART intensification studies have been unable to reduce low-level viremia, suggesting that this phenomena is a result of stochastic activation of latently infected cells, rather than continued rounds of replication (Dinoso et al, 2009;McMahon et al, 2010;Anderson et al, 2011;Gandhi et al, 2012).…”