Decreased Activated CD4⁺ T Cell Repertoire Diversity After Antiretroviral Therapy in HIV-1/HCV Coinfection Correlates with CD4⁺ T Cell Recovery

Dysfunctional immune activation accumulates during chronic viral infection and contributes to disease pathogenesis. In HIV-1, immune activation is exacerbated by concurrent infection with hepatitis C virus (HCV), accelerating depletion of CD4⁺ T cells. HIV-1 suppression with antiretroviral therapy (ART) generally reconstitutes CD4⁺ T cell counts, while also reducing the proportion that is activated. Whether this immune reconstitution also reduces the complexity of the CD4⁺ T cell population is unknown. We sought to characterize the relationship between activated CD4⁺ T cell repertoire diversity and immune reconstitution following ART in HIV-1/HCV coinfection. We extracted T cell receptor (TCR) sequences from RNA sequencing data obtained from activated CD4⁺ T cells of HIV-1/HCV coinfected individuals before and after treatment with ART (clinical trial NCT01285050). There was notable heterogeneity in both the extent of CD4⁺ T cell reconstitution and in the change in activated CD4⁺ TCR repertoire diversity following ART. Decreases in activated CD4⁺ TCR repertoire diversity following ART were predictive of the degree of CD4⁺ T cell reconstitution. The association of decreased activated CD4⁺ TCR repertoire diversity and improved CD4⁺ T cell reconstitution may represent loss of nonspecifically activated TCR clonotypes, and possibly selective expansion of specifically activated CD4⁺ clones. These results provide insight into the dynamic relationship between activated CD4⁺ TCR diversity and CD4⁺ T cell recovery of HIV-1/HCV coinfected individuals after suppression of HIV-1 viremia.