Dominant CD4+ T cell receptors remain stable throughout antiretroviral therapy-mediated immune restoration in people with HIV

Alexis Sponaugle; Ann Marie K Weideman; Jolene Ranek; Gatphan Atassi; JoAnn Kuruc; Adaora A Adimora; Nancie M Archin; Cynthia Gay; Daniel R Kuritzkes; David M Margolis; Benjamin G Vincent; Natalie Stanley; Michael G Hudgens; Joseph J Eron; Nilu Goonetilleke

doi:10.1016/j.xcrm.2023.101268

Dominant CD4⁺ T cell receptors remain stable throughout antiretroviral therapy-mediated immune restoration in people with HIV

Cell Rep Med. 2023 Nov 21;4(11):101268. doi: 10.1016/j.xcrm.2023.101268. Epub 2023 Nov 9.

Authors

Affiliations

¹ Department of Microbiology & Immunology, UNC Chapel Hill, Chapel Hill, NC, USA.
² Department of Biostatistics, UNC Chapel Hill, Chapel Hill, NC, USA; Center for AIDS Research, School of Medicine, UNC Chapel Hill, Chapel Hill, NC, USA.
³ Computational Medicine Program, UNC Chapel Hill, Chapel Hill, NC, USA; Curriculum in Bioinformatics and Computational Biology, UNC Chapel Hill, Chapel Hill, NC, USA.
⁴ Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, NC, USA.
⁵ Department of Medicine, UNC Chapel Hill, Chapel Hill, NC, USA.
⁶ Center for AIDS Research, School of Medicine, UNC Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, UNC Chapel Hill, Chapel Hill, NC, USA; Department of Epidemiology, Gillings School of Global Public Health, UNC Chapel Hill, Chapel Hill, NC, USA.
⁷ Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Department of Microbiology & Immunology, UNC Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, UNC Chapel Hill, Chapel Hill, NC, USA.
⁹ Department of Microbiology & Immunology, UNC Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, UNC Chapel Hill, Chapel Hill, NC, USA; Curriculum in Bioinformatics and Computational Biology, UNC Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Computational Medicine Program, UNC Chapel Hill, Chapel Hill, NC, USA; Department of Computer Science, UNC Chapel Hill, Chapel Hill, NC, USA.
¹¹ Department of Microbiology & Immunology, UNC Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, UNC Chapel Hill, Chapel Hill, NC, USA. Electronic address: [email protected].

Abstract

In people with HIV (PWH), the post-antiretroviral therapy (ART) window is critical for immune restoration and HIV reservoir stabilization. We employ deep immune profiling and T cell receptor (TCR) sequencing and examine proliferation to assess how ART impacts T cell homeostasis. In PWH on long-term ART, lymphocyte frequencies and phenotypes are mostly stable. By contrast, broad phenotypic changes in natural killer (NK) cells, γδ T cells, B cells, and CD4⁺ and CD8⁺ T cells are observed in the post-ART window. Whereas CD8⁺ T cells mostly restore, memory CD4⁺ T subsets and cytolytic NK cells show incomplete restoration 1.4 years post ART. Surprisingly, the hierarchies and frequencies of dominant CD4 TCR clonotypes (0.1%-11% of all CD4⁺ T cells) remain stable post ART, suggesting that clonal homeostasis can be independent of homeostatic processes regulating CD4⁺ T cell absolute number, phenotypes, and function. The slow restoration of host immunity post ART also has implications for the design of ART interruption studies.

Keywords: HIV; T cell receptor; TCR sequencing; antiretroviral therapy; homeostasis; human; latency; mass cytometry.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Anti-Retroviral Agents / therapeutic use
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
HIV Infections* / drug therapy
Humans
Immune Reconstitution*
Receptors, Antigen, T-Cell

Substances

Anti-Retroviral Agents
Receptors, Antigen, T-Cell

Abstract

Publication types

MeSH terms

Substances

Grants and funding