Activation of CXCR3+ Tfh cells and B cells in lymph nodes during acute HIV-1 infection correlates with HIV-specific antibody development

Lymph node T follicular helper (Tfh) cells and germinal center (GC) B cells are critical to generate potent antibodies but are rarely possible to study in humans. To understand how Tfh/GC B-cell interactions during acute HIV-1 infection (AHI) impact the generation of HIV-specific antibodies, we performed a unique cross-sectional analysis of inguinal lymph node biopsies taken prior to antiretroviral therapy (ART) initiation in AHI. Although total Tfh and GC B cell frequencies did not change during AHI, increased frequencies of proliferating Th1-like CXCR3+ Tfh, CXCR3+ non-GC B cells, and total CXCR3+ GC B cells correlated with gp120-specific IgG antibody levels in AHI. Frequencies of proliferating CXCR3+ Tfh in AHI also correlated with gp120-specific IgG antibody levels after 48 weeks of ART, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and increased antibody binding to infected cells after ART. Importantly, while beneficial for antibody development, CXCR3+ Tfh cells were also infected by HIV-1 at higher frequencies than their CXCR3− counterparts and may contribute to the initial dissemination of HIV-1 in follicles. Together, these data suggest that activation of CXCR3+ Tfh cells is associated with induction of the germinal center response and subsequent antibody development, making these cells an important target for future therapeutic interventions.