HCV-specific CD4⁺ T-cells are susceptible to HIV-1 and contribute to viral persistence during antiretroviral therapy.

Abstract

Antiretroviral therapy (ART) reduces human immunodeficiency virus type 1 (HIV-1) replication to undetectable levels but does not eliminate HIV-1 reservoirs, which persist in memory CD4⁺ T-cells of various antigenic specificities. Hepatitis C virus (HCV) coinfection is associated with an increase in HIV-DNA burden, but whether HCV-specific CD4⁺ T-cells are susceptible to HIV-1 infection and harbour replication-competent HIV reservoirs upon HCV resolution is unknown. In this cross-sectional study, we examined the impact of HCV infection on CD4⁺ T-cell susceptibility to HIV-1 infection in vitro and reservoir persistence during ART in subjects with chronic HCV infection and uninfected controls (n = 20/group) and longitudinally in one ART-treated HCV⁺HIV⁺ individual who spontaneously resolved multiple episodes of HCV infection. Memory CD4⁺ T-cells from subjects with chronic HCV exhibited superior permissiveness to productive HIV-1 infection in vitro (p = 0.03) compared to uninfected. This was proportional to plasma HCV-RNA levels (p = 0.046; r = 0.491). HCV-specific CD4⁺ T-cells distinguished from other antigenic specificities (e.g., Cytomegalovirus) by a CCR5⁺ (HIV-1 co-receptor), CXCR6⁺ (liver-homing marker) and CCR6⁺ (Th17 marker) phenotype and supported productive HIV-1 infection in vitro. In the HCV⁺ HIV⁺ subject, HCV-specific CD4⁺ T-cells carried replication-competent reservoir during acute HCV reinfection, with integrated HIV-DNA persisting in these cells upon HCV clearance. We provide evidence that HCV-specific CD4⁺ T-cells are targets of integrative HIV-1 infection and carry proviruses that persist during ART despite HCV resolution. Canadian Institutes of Health Research (CIHR) (PJT-173467, PJT-153052, PJT-178127, PJT-195736, HB2-164064, BR4-197730, MOP135260, FDN-143270, CTN222 and NHC142832), the National Institutes of Health (NIH) (U19AI159819), and Fonds de recherche du Québec-Santé (FRQS)-Réseau SIDA/maladies infectieuses.