Year: 2026
Type: article
Study design: Case Report
Abstract: ABSTRACT Background HIV-1 RNA typically declines rapidly after initiation of antiretroviral therapy (ART); often reaching undetectable levels within a few weeks and remaining undetectable by standard assays. However, some patients on ART have persistent nonsuppressible viremia (NSV) that does not respond to treatment optimization or intensification. NSV can emerge at the time of ART initiation ( primary NSV ) or after being ART-suppressed ( secondary NSV ). Here, we examine mechanisms producing primary NSV in four people on ART. Methods Blood samples were collected from four participants who, despite being adherent to ART, required approximately a year or more to become virologically suppressed. Viral RNA and proviral DNA genomes were sequenced to examine HIV-1 drug resistance, genome intactness and genetic diversity. The ability of HIV-1 Envs to facilitate efficient entry into cells expressing low levels of CD4 (a proxy for macrophage tropism) was assessed. Results Before ART, the blood contained HIV-1 RNA genomes that were adapted to replication in CD4+ T cells and rapidly decayed after ART initiation. During ART, the blood contained HIV-1 genomes that were drug sensitive, genetically diverse, macrophage-tropic, not evolving and often had defects in vpr . Conclusions Our results suggest that in individuals with primary NSV , ART stopped virus replication, but large pools of long-lived, HIV-infected macrophage continued to produce virus. This is mechanistically distinct from secondary NSV produced by CD4+ T cell clones. In addition, defects in vpr independently accumulation in macrophage-tropic lineages found in three participants, suggesting that vpr may impact survival of, or virus production from, HIV-infected macrophage. SUMMARY People with HIV-1 on ART can experience persistent, nonsuppressible viremia (NSV). We identified four people with a previously uncharacterized form of NSV that emerged at the time of ART initiation (primary NSV) and is notable for its genetic diversity, drug sensitivity, and macrophage tropism. This is mechanistically distinct from previously described cases of NSV produced by CD4+ T cells in people who were previously ART-suppressed (secondary NSV).
Authors: Matthew J Moeser, Nathan Long, Laura Kincer, Ann M Dennis, Joseph Eron, David Wohl, Claire E Farel, Dirk P Dittmer, Linda Pluta, Julie Nelson, Abbas Mohammadi, Behzad Etemad, Jonathan Z Li, Hugh McGann, Erasmus Smit, Meredith Clement, Tat Yau, Prema Menezes, Natalie M Bowman, Shuntai Zhou, Sarah B Joseph
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1467100060, G1620350588, G6841548350, Development and Use of Novel SHIVs Bearing Clinically Relevant HIV-1 Envs for Examining HIV Persistence and Eradication in the CNS of Nonhuman Primates, G9000131203, G9000196861, G9000229802, Identifying Roadblocks to Antigen Expression and Enhancing Killing of HIV-Infected Cells That Are Refractory to Clearance, High-Definition Characterization of the Persistence and Perturbation of the HIV Reservoir, Viral Oncogenesis, Latency, and Replication, Collaboratory of AIDS Researchers for Eradication (CARE), The University of North Carolina Center for AIDS Research, Cancer Center Support Grant
OpenAlex ID: W4414048613