Early Initiation of Antiretroviral Therapy Preserves the Metabolic Function of CD4⁺ T Cells in Subtype C Human Immunodeficiency Virus 1 Infection

Background. Immune dysfunction often persists in people living with human immunodeficiency virus (HIV) who are on antiretroviral therapy (ART), clinically manifesting as HIV-1-associated comorbid conditions. Early ART initiation may reduce incidence of HIV-1-associated immune dysfunction and comorbid conditions. Immunometabolism is a critical determinant of functional immunity. We investigated the effect of HIV-1 infection and timing of ART initiation on CD4(+) T cell metabolism and function.Methods. Longitudinal blood samples from people living with HIV who initiated ART during hyperacute HIV-1 infection (HHI; before peak viremia) or chronic HIV-1 infection (CHI) were assessed for the metabolic and immune functions of CD4(+) T cells. Metabolite uptake and mitochondrial mass were measured using fluorescent analogues and MitoTracker Green accumulation, respectively, and were correlated with CD4(+) T cell effector functions.Results. Initiation of ART during HHI prevented dysregulation of glucose uptake by CD4(+) T cells, but glucose uptake was reduced before and after ART initiation in CHI. Glucose uptake positively correlated with interleukin-2 and tumor necrosis factor-alpha production by CD4(+) T cells. CHI was associated with elevated mitochondrial mass in effector memory CD4(+) T cells that persisted after ART and correlated with PD-1 expression.Conclusions. ART initiation in HHI largely prevented metabolic impairment of CD4(+) T cells. ART initiation in CHI was associated with persistently dysregulated immunometabolism of CD4(+) T cells, which was associated with impaired cellular functions and exhaustion.