Open AccessIncreased homeostatic cytokines and stability of HIV-infected memory CD4 T-cells identify individuals with suboptimal CD4 T-cell recovery on-ART
Author(s) -
María Pino,
Susan Pereira Ribeiro,
Amélie Pagliuzza,
Khader Ghneim,
Anum N. Khan,
Emily S. Ryan,
Justin Harper,
Colin T. King,
Sarah Welbourn,
Luca Micci,
Sol Aldrete,
Keith A. Delman,
Theron Stuart,
Michael Lowe,
Jason M. Brenchley,
Cynthia A. Derdeyn,
Kirk A. Easley,
Rafick Pierre Sékaly,
Nicolas Chomont,
Mirko Paiardini,
Vincent C. Marconi
Publication year - 2021
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1009825
Subject(s) - tigit , homeostasis , immunology , t cell , cell , cd4 t cell , antiretroviral therapy , memory t cell , immune system , medicine , viral load , chemistry , human immunodeficiency virus (hiv) , biology , microbiology and biotechnology , biochemistry
Clinical outcomes are inferior for individuals with HIV having suboptimal CD4 T-cell recovery during antiretroviral therapy (ART). We investigated if the levels of infection and the response to homeostatic cytokines of CD4 T-cell subsets contributed to divergent CD4 T-cell recovery and HIV reservoir during ART by studying virologically-suppressed immunologic responders (IR, achieving a CD4 cell count >500 cells/μL on or before two years after ART initiation), and virologically-suppressed suboptimal responders (ISR, did not achieve a CD4 cell count >500 cells/μL in the first two years after ART initiation). Compared to IR, ISR demonstrated higher levels of HIV-DNA in naïve, central (CM), transitional (TM), and effector (EM) memory CD4 T-cells in blood, both pre- and on-ART, and specifically in CM CD4 T-cells in LN on-ART. Furthermore, ISR had higher pre-ART plasma levels of IL-7 and IL-15, cytokines regulating T-cell homeostasis. Notably, pre-ART PD-1 and TIGIT expression levels were higher in blood CM and TM CD4 T-cells for ISR; this was associated with a significantly lower fold-changes in HIV-DNA levels between pre- and on-ART time points exclusively on CM and TM T-cell subsets, but not naïve or EM T-cells. Finally, the frequency of CM CD4 T-cells expressing PD-1 or TIGIT pre-ART as well as plasma levels of IL-7 and IL-15 predicted HIV-DNA content on-ART. Our results establish the association between infection, T-cell homeostasis, and expression of PD-1 and TIGIT in long-lived CD4 T-cell subsets prior to ART with CD4 T-cell recovery and HIV persistence on-ART.