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

TY - JOUR

T1 - Early Initiation of Antiretroviral Therapy Preserves the Metabolic Function of CD4+ T Cells in Subtype C Human Immunodeficiency Virus 1 Infection

AU - Naidoo, Kewreshini K

AU - Highton, Andrew J

AU - Baiyegunhi, Omolara O

AU - Bhengu, Sindiswa P

AU - Dong, Krista L

AU - Bunders, Madeleine J

AU - Altfeld, Marcus

AU - Ndung'u, Thumbi

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

PY - 2024/3/14

Y1 - 2024/3/14

N2 - 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-α 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.

AB - 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-α 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.

KW - Anti-Retroviral Agents/therapeutic use

KW - CD4-Positive T-Lymphocytes

KW - Glucose

KW - HIV Infections

KW - HIV-1

KW - Humans

U2 - 10.1093/infdis/jiad432

DO - 10.1093/infdis/jiad432

M3 - SCORING: Journal article

C2 - 37804102

VL - 229

SP - 753

EP - 762

JO - J INFECT DIS

JF - J INFECT DIS

SN - 0022-1899

IS - 3

ER -