Codelivery of envelope protein in alum with MVA vaccine induces CXCR3- biased CXCR5⁺ and CXCR5^- CD4 T cell responses in rhesus macaques

The goal of an HIV vaccine is to generate robust and durable protective Ab. Vital to this goal is the induction of CD4⁺ T follicular helper (T_FH) cells. However, very little is known about the T_FH response to HIV vaccination and its relative contribution to magnitude and quality of vaccine-elicited Ab titers. In this study, we investigated these questions in the context of a DNA/modified vaccinia virus Ankara SIV vaccine with and without gp140 boost in aluminum hydroxide in rhesus macaques. In addition, we determined the frequency of vaccine-induced CD4⁺ T cells coexpressing chemokine receptor, CXCR5 (facilitates migration to B cell follicles) in blood and whether these responses were representative of lymph node T_FH responses. We show that booster modified vaccinia virus Ankara immunization induced a distinct and transient accumulation of proliferating CXCR5⁺ and CXCR5^- CD4 T cells in blood at day 7 postimmunization, and the frequency of the former but not the latter correlated with T_FH and B cell responses in germinal centers of the lymph node. Interestingly, gp140 boost induced a skewing toward CXCR3 expression on germinal center T_FH cells, which was strongly associated with longevity, avidity, and neutralization potential of vaccine-elicited Ab response. However, CXCR3⁺ cells preferentially expressed the HIV coreceptor CCR5, and vaccine-induced CXCR3⁺CXCR5⁺ cells showed a moderate positive association with peak viremia following SIV251 infection. Taken together, our findings demonstrate that vaccine regimens that elicit CXCR3-biased T_FH cell responses favor Ab persistence and avidity but may predispose to higher acute viremia in the event of breakthrough infections.