T cells with high expression of PD-1 (PD-1HI), a marker of T cell exhaustion, persist among people with HIV on antiretroviral therapy (ART).To assess whether PD-1HI expression may reflect exhaustion of T cells targeting HIV, we determined whether the frequency of PD-1HI T cells is associated with reduced HIV-specific T cell responses.
Peripheral blood mononuclear cells from participants in ACTG A5321 with documented viral suppression on ART for at least 4 years (N=93) were analyzed for percentage of CD4+ and CD8+ T cells with PD-1HI expression as determined by flow cytometry. HIV-specific T cell immunity was determined by IFNγ ELISPOT in response to Gag, Pol, Env, Nef/Tat/Rev, Vpr/Vpf/Vpu peptide pools as well as CMV-pp65 and EBV BZLF-1 peptide pools.
Frequencies of both CD4+ and CD8+ PD-1HI T cells pre-ART significantly correlated with levels of pre-ART HIV-1 RNA (r=0.28, p=0.01 and r=0.24, p=0.03, respectively; Spearman correlation). At 4 years of viral suppression with a median CD4+ T cell count of 681 cells/mm3, participants had the same median (Q1-Q3) frequencies of PD-1HI CD4+ (0.3%; 0.1-0.5) and CD8+ (0.3%; 0.2-0.6) T cells. Both CD4+ and CD8+ PD-1HI T cell frequencies showed negative correlations with IFNγ responses to all HIV peptides, although not all reached statistical significance. The %CD4+ PD-1HI T cells had significant negative correlations with Gag- and Env-specific responses (r= -0.24, p=0.04 and r= -0.32, p=0.005; Figure 1). A modest negative trend was observed with Pol (r= -0.2; p=0.08) and combined Vpr/Vif/Vpu (r= -0.22, p=0.07) peptide pools. The %CD8+ PD-1HI T cells showed a trend for a negative correlation with the same HIV peptide pools (Gag, r= -0.22, p=0.06; Env, r= -0.21, p=0.07). By contrast, no significant correlations were observed between PD-1HI T cell frequencies and responses to CMV or EBV peptides.
Peripheral blood frequencies of PD-1HI CD4+ T cells of people with HIV on ART were negatively associated with HIV-specific IFNγ responses, but not with CMV or EBV responses. These findings suggest that the PD-1HI CD4+ T cell subset contains HIV-specific cells that have decreased helper function and should be targeted to reverse immune dysfunction and improve immune control of HIV.