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

Abstract

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.

Importance: Early initiation of antiretroviral therapy (ART) is important to limit the seeding of the long-lasting HIV-1 reservoir; however, it also precludes the development of HIV-specific antibodies that can help control the virus if ART is stopped. Antibody development occurs within germinal centers in the lymph node and requires activation of both antigen-specific B cells and T follicular helper cells (Tfh), a specialized CD4⁺ cell that provides B cell help. To understand how early ART initiation may prohibit antibody development, we analyzed the frequencies and activation status of Tfh and B cells in lymph node biopsies collected in the different stages of acute HIV-1 infection. Our data suggest that decreased antibody development after early ART initiation may be due to limited germinal center development at the time of treatment and that new interventions that target activation of CXCR3⁺ Tfh may be beneficial to increase long-term HIV-specific antibody levels.