Discordance between HIV-1 Population in Plasma at Rebound after Structured Treatment Interruption and Archived Provirus Population in Peripheral Blood Mononuclear Cells.

Antiretroviral therapy (ART) can sustain the suppression of plasma viremia to below detection levels. Infected individuals undergoing a treatment interruption exhibit rapid viral rebound in plasma viremia which is fueled by cellular reservoirs such as CD4+ T cells, myeloid cells, and potentially uncharacterized cellular sources. Interrogating the populations of viruses found during analytical treatment interruption (ATI) can give insights into the biologically competent reservoirs that persist under effective ART as well as the nature of the cellular reservoirs that enable viral persistence under ART. We interrogated plasma viremia from four rare cases of individuals undergoing sequential ATIs. We performed next-generation sequencing (NGS) on cell-associated viral DNA and cell-free virus to understand the interrelationship between sequential ATIs as well as the relationship between viral genomes in circulating peripheral blood mononuclear cells (PBMCs) and RNA from rebound plasma. We observed population differences between viral populations recrudescing at sequential ATIs as well as divergence between viral sequences in plasma and those in PBMCs. This indicated that viruses in PBMCs were not a major source of post-ATI viremia and highlights the role of anatomic reservoirs in post-ATI viremia and viral persistence. IMPORTANCE Even with effective ART, HIV-1 persists at undetectable levels and rebounds in individuals who stop treatment. Cellular and anatomical reservoirs ignite viral rebound upon treatment interruption, remaining one of the key obstacles for HIV-1 cure. To further examine HIV-1 persistence, a better understanding of the distinct populations that fuel viral rebound is necessary to identify and target reservoirs and the eradication of HIV-1. This study investigates the populations of viruses found from proviral genomes from PBMCs and plasma at rebound from a unique cohort of individuals who underwent multiple rounds of treatment interruption. Using NGS, we characterized the subtypes of viral sequences and found divergence in viral populations between plasma and PBMCs at each rebound, suggesting that distinct viral populations appear at each treatment interruption.

The Interplay of HIV-1 and Macrophages in Viral Persistence.

HIV-1 has evolved mechanisms to evade host cell immune responses and persist for lifelong infection. Latent cellular reservoirs are responsible for this persistence of HIV-1 despite the powerful effects of highly active antiretroviral therapies (HAART) to control circulating viral load. While cellular reservoirs have been extensively studied, much of these studies have focused on peripheral blood and resting memory CD4+ T cells containing latent HIV-1 provirus; however, efforts to eradicate cellular reservoirs have been stunted by reservoirs found in tissues compartments that are not easily accessible. These tissues contain resting memory CD4+ T cells and tissue resident macrophages, another latent cellular reservoir to HIV-1. Tissue resident macrophages have been associated with HIV-1 infection since the 1980s, and evidence has continued to grow regarding their role in HIV-1 persistence. Specific biological characteristics play a vital role as to why macrophages are latent cellular reservoirs for HIV-1, and in vitro and in vivo studies exhibit how macrophages contribute to viral persistence in individuals and animals on antiretroviral therapies. In this review, we characterize the role and evolutionary advantages of macrophage reservoirs to HIV-1 and their contribution to HIV-1 persistence. In acknowledging the interplay of HIV-1 and macrophages in the host, we identify reasons why current strategies are incapable of eliminating HIV-1 reservoirs and why efforts must focus on eradicating reservoirs to find a future functional cure.