The ecto-enzyme CD38 modulates CD4 T cell immunometabolic responses and participates in HIV pathogenesis.

Despite abundant evidence correlating T cell CD38 expression and HIV infection pathogenesis, its role as a CD4 T cell immunometabolic regulator remains unclear. We find that CD38's extracellular glycohydrolase activity restricts metabolic reprogramming after TCR-engaging stimulation in Jurkat T CD4 cells, together with functional responses, while reducing intracellular NAD and NMN concentrations. Selective elimination of CD38's ectoenzyme function licenses them to decrease the OCR/ECAR ratio upon TCR signaling and to increase cycling, proliferation, survival, and CD40L induction. Pharmacological inhibition of ectoCD38 catalytic activity in memory CD4 T cells from chronic HIV-infected patients rescued TCR-triggered responses, including differentiation and effector functions, while reverting abnormally increased basal glycolysis, cycling, and spontaneous pro-inflammatory cytokine production. Additionally, ecto-CD38 blockage normalized basal and TCR-induced mitochondrial morpho-functionality, while increasing respiratory capacity in cells from HIV+ patients and healthy individuals. Ectoenzyme CD38's immunometabolic restriction of TCR-involving stimulation is relevant to CD4 T cell biology and to the deleterious effects of CD38 overexpression in HIV disease.

Exceptional T CD4+ Recovery Post-antiretroviral Is Linked to a Lower HIV Reservoir with a Specific Immune Differentiation Pattern.

We present a cohort of individuals who reached CD4+ T cell counts of greater than 1,000 cells/mm3 (Hypers) after starting antiretroviral treatment (ART) and compared them with those who reached between 350 and 999 CD4+ T cells/mm3 (Concordants). Demographic data, immune recovery kinetics, T CD4+ subset phenotypes, and integrated HIV DNA were analyzed. Data from individuals living with HIV on their first ART regimen and after 48 months of follow-up were obtained. Immune phenotype by Flow Cytometry analysis on whole blood was performed, cytokines were measured, and integrated HIV-1 DNA was measured by polymerase chain reaction. From a total of 424 individuals, 26 Hypers (6.1%), 314 Concordants (74.1%), and 84 (19.8%) discordants were identified. Hypers had a higher proportion of CD4+-naive (Nv) T cells (37.6 vs. 24.8, p < .05), and a low proportion of CD4+ effector memory T cells (27.9 vs. 39.4, p < .05), with similar results found in CD8+ T cells. Hypers demonstrated a higher percentage of CD4+CD45RA+CD31neg cells with a lower response to interleukin-2 stimulation and a lower integrated HIV-1 DNA/CD4 ratio (1.2 vs. 2.89, p < .05). In Hypers, T cell recovery occurs very early after initiation of ART. Following this initial recovery state, their CD4+ T cell level homeostasis seems to be driven by nonthymic-central-Nv cells. This exceptional recovery is associated with a lower HIV reservoir, which may be related to an increase in noninfected CD4+ T cells. These patients could then be eligible candidates for cure trials.