Background: Methamphetamine (Meth) is a highly addictive stimulant that is frequently used by HIV-infected (HIV+) individuals and contributes to worse clinical outcomes. Chronic HIV infection is associated with persistent T cell activation and immune exhaustion, defined by the upregulation of negative checkpoint receptors (PD-1, TIM-3, TIGIT).Given that Meth exposure adversely impacts host adaptive immunity, mechanistic insight into T cell perturbations may provide avenues to overcome these deleterious effects. Here we examined the associations between Meth use and
T cell activation, senescence and immune exhaustion in HIV+ individuals on stable antiretroviral therapy (ART).
Methods: Available data of self-reported methamphetamine use were drawn cross-sectionally from study participants in the Hawaii Aging with HIV Cardiovascular Study. Individuals were classified into 3 groups:
(1) never-used,
(2) recent-users (last use was less than or equal to 1 year ago), and
(3) remote-users (last use was greater than 1 year ago).
Markers of CD4+ and CD8+ T cell activation (CD38+HLA-DR+), maturation (CD28-CD57+), and immune exhaustion (PD-1, TIM-3 and TIGIT expression) were measured in cryopreserved peripheral blood mononuclear cells by flow cytometry. Median percent frequencies of T cell subsets were calculated and compared between groups by the Kruskal-Wallis test.
Results: 43 HIV+ participants had available T cell immunophenotype assessments: 88% male; 84% with plasma viral load < 50 copies/ml; 31 (72%) never-used, 6 (14%) remote-users and 6 (14%) recent-users. CD4 T cell counts were significantly lower in the recent-users (median (IQR): 229 cells/uL (165, 357)) compared to remote-users (524 cells/uL (424, 702)) and never-used (548 cells/uL (404, 700)), p< 0.05. Frequencies of single TIGIT+ CD8 T cells and TIGIT+ or PD-1+ and dual TIGIT+PD1+ CD4 T cell were significantly higher in the recent-users compared to never-used and remote-users (all p < 0.05). No differences among groups were seen for T cell activation or senescence.
Conclusions: Recent Meth users demonstrated the highest levels of CD4 and CD8 T cell exhaustion compared to never-used and remote-users. Meth-induced T cell exhaustion could potentially compromise immune effector responses and sustain viral persistence; hence Meth use should be avoided in HIV+ individuals and strategies targeting TIGIT or PD-1 may be prioritized in this population.