Increased homeostatic cytokines and stability of HIV-infected memory CD4 T-cells identify individuals with suboptimal CD4 T-cell recovery on-ART

Abstract

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.

Comparative Transcriptional Analysis Identified Characteristic Genes and Patterns in HIV-Infected Immunological Non-Responders

“…Previous studies had shown the relationship between HIV reservoirs and suboptimal CD4 recovery (55)(56)(57). Interestingly, a recent study showed that the increased homeostatic cytokine levels, especially IL-7 and IL-15, were also associated with HIV reservoirs in T-cell subsets and poor immune reconstitution during cART (58). The role of proinflammatory and homeostatic cytokines in the connection between viral reservoirs recovery and the immunopathogenesis of chronic IA had been reported (59,60).…”

Epigenome-wide epidemiologic studies of human immunodeficiency virus infection, treatment, and disease progression

“…In contrast, another study found that in six PWH on ART without detectable viremia, CpG methylation of the HIV 5′ LTR was 20%, 30%, 48%, 71%, 96%, and 100%—compared with < 0.1% in a control group of viremic patients [ 29 ]. These discordant findings suggest that factors such as subtypes of CD4 + T cells [ 30 ], history of infection, duration and type of ART, degrees of turnover of latently infected CD4 + T cells, and inclusion of unintegrated HIV DNA may play a significant role in the variation of DNAm, viral persistence, and latency.…”

Optimizing the antiretroviral treatment focusing on long-term effectiveness and a person-centred approach. Consensus Guidance Using a Delphi Process

“…The panel did not reach an agreement about the utility of using inflammation or immune-activation markers in daily clinical practice. In fact, the study of such markers has been proposed by some panelists to further refine decision-making algorithms, with the aim of defining safer and more tailored therapies [32][33][34][35][36][37][38]. However, the clinical relevance of these markers is currently unproven, leading most respondents to express disagreement with their use in clinical practice.…”