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

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.