Natural Killer Cell Receptors and Ligands Are Associated With Markers of HIV-1 Persistence in Chronically Infected ART Suppressed Patients.

Abstract

The latent HIV-1 reservoir represents a major barrier to achieving a long-term antiretroviral therapy (ART)-free remission or cure for HIV-1. Natural Killer (NK) cells are innate immune cells that play a critical role in controlling viral infections and have been shown to be involved in preventing HIV-1 infection and, in those who are infected, delaying time to progression to AIDS. However, their role in limiting HIV-1 persistence on long term ART is still uncharacterized. To identify associations between markers of HIV-1 persistence and the NK cell receptor-ligand repertoire, we used twin mass cytometry panels to characterize the peripheral blood NK receptor-ligand repertoire in individuals with long-term antiretroviral suppression enrolled in the AIDS Clinical Trial Group A5321 study. At the time of testing, participants had been on ART for a median of 7 years, with virological suppression <50 copies/mL since at most 48 weeks on ART. We found that the NK cell receptor and ligand repertoires did not change across three longitudinal samples over one year-a median of 25 weeks and 50 weeks after the initial sampling. To determine the features of the receptor-ligand repertoire that associate with markers of HIV-1 persistence, we performed a LASSO normalized regression. This analysis revealed that the NK cell ligands CD58, HLA-B, and CRACC, as well as the killer cell immunoglobulin-like receptors (KIRs) KIR2DL1, KIR2DL3, and KIR2DS4 were robustly predictive of markers of HIV-1 persistence, as measured by total HIV-1 cell-associated DNA, HIV-1 cell-associated RNA, and single copy HIV-RNA assays. To characterize the roles of cell populations defined by multiple markers, we augmented the LASSO analysis with FlowSOM clustering. This analysis found that a less mature NK cell phenotype (CD16+CD56dimCD57-LILRB1-NKG2C-) was associated with lower HIV-1 cell associated DNA. Finally, we found that surface expression of HLA-Bw6 measured by CyTOF was associated with lower HIV-1 persistence. Genetic analysis revealed that this was driven by lower HIV-1 persistence in HLA-Bw4/6 heterozygotes. These findings suggest that there may be a role for NK cells in controlling HIV-1 persistence in individuals on long-term ART, which must be corroborated by future studies.

• Authors: Geoffrey T Ivison, Elena Vendrame, Giovanny J Martínez-Colón, Thanmayi Ranganath, Rosemary Vergara, Nancy Q Zhao, Maureen P Martin, Sean C Bendall, Mary Carrington, Joshua C Cyktor, Deborah K McMahon, Joseph Eron, R Brad Jones, John W Mellors, Ronald J Bosch, Rajesh T Gandhi, Susan Holmes, Catherine A Blish, ACTG 5321 Team
• Journal: Frontiers in cellular and infection microbiology (Front Cell Infect Microbiol) Vol. 12 Pg. 757846 ( 2022) ISSN: 2235-2988 [Electronic] Switzerland
• PMID: 35223535 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2022 Ivison, Vendrame, Martínez-Colón, Ranganath, Vergara, Zhao, Martin, Bendall, Carrington, Cyktor, McMahon, Eron, Jones, Mellors, Bosch, Gandhi, Holmes, Blish and The ACTG 5321 Team.

Chemical References

• Ligands
• Receptors, Natural Killer Cell

Topics

• HIV Infections (drug therapy)
• HIV-1
• Humans
• Ligands
• Receptors, Natural Killer Cell (metabolism, therapeutic use)
• Virus Latency