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

Abstract

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.

Keywords: CD4-positive T lymphocytes; HIV; T cell; antigen; coinfection; hepatitis C; immune reconstitution; receptors.

FIG. 1.

CD4⁺ T cell counts before and after HIV-1 suppression. (A) CD4⁺ T cell counts were measured in the peripheral blood of HIV-1/HCV coinfected participants (n = 18) at baseline and after HIV-1 suppression with ART. Paired t-test, p < 0.01. (B) The change in CD4⁺ T cell count from baseline to HIV-1 suppression was calculated for each study participant. (C) The change in the frequency of activated CD4⁺ T cells was compared to the change in total CD4⁺ T cell count. ART, antiretroviral therapy; HCV, hepatitis C virus; R, Kendall rank correlation coefficient.

FIG. 2.

TCR repertoire richness before and after HIV-1 suppression. TCR β chain richness was plotted against TCR α chain richness for each participant at baseline (A) and after HIV-1 suppression (B). Richness was estimated at both the TCR β chain (C) and the TCR α chain (D) for each participant (n = 18) at baseline and after HIV-1 suppression. Wilcoxon signed rank test. ns, not significant; TCR, T cell receptor.

FIG. 3.

Change in richness as a function of change in CD4⁺ T cell count. The change in richness (Chao1 estimator) from baseline to after HIV-1 suppression for each participant (n = 18) was plotted against the change in CD4⁺ T cell count over this same time period. Richness estimates were done at both the TCR β chain (A) and the TCR α chain (B). Richness was also estimated using a randomly selected subsample of RNA sequences to control for differences in sequencing depth. Richness was estimated from the subsampled sequences at baseline and after HIV-1 suppression and estimates were made at both the TCR β chain (C) and the TCR α chain (D). Statistical significance was determined using p < 0.05 as cutoff.

FIG. 4.

Change in CD4⁺ T cell counts and TCR richness as a function of absolute CD4⁺ T cell counts. The change in CD4⁺ T cell count from baseline to after HIV-1 suppression for each participant (n = 18) was plotted against the absolute CD4⁺ T cell count at baseline (A). The change in TCR richness (Chao1 estimator) from baseline to after HIV viral suppression for each participant (n = 18) was compared to the absolute CD4⁺ T cell count at baseline. Richness estimates were done at both the TCR β chain (B) and the TCR α chain (C). The change in CD4⁺ T cell count from baseline to after HIV-1 suppression for each participant (n = 18) was plotted against the absolute CD4⁺ T cell count after HIV-1 suppression (D). The change in TCR richness was plotted against the absolute CD4⁺ T cell count after HIV viral suppression, with richness estimates again being done at both the TCR β chain (E) and the TCR α chain (F). Statistical significance was determined using p < 0.05 as cutoff.