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PD-1HI CD4+ T CELLS ARE ASSOCIATED WITH REDUCED HIV-SPECIFIC RESPONSES
Bernard J. Macatangay1, Rajesh T. Gandhi2, R. Brad Jones3, Deborah McMahon1, Allison S. Thomas4, Christina Lalama5, Ronald Bosch5, Luann Borowski1, Evelyn Hogg6, Joseph J. Eron7, John W. Mellors1, Charles Rinaldo1
1University of Pittsburgh, Pittsburgh, PA, USA,2Harvard Medical School, Boston, MA, USA,3New York Presbyterian Hospital, New York, NY, USA,4Boston University, Boston, MA, USA,5Harvard University, Boston, MA, USA,6Social & Scientific Systems, Silver Spring, MD, USA,7University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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.