gastrointestinal tract germinal centers in the earliest stages of HIV-1 infection.

Polyclonal B cell differentiation and loss of gastrointestinal tract germinal centers in the earliest stages of HIV-1 infection.

The antibody response to HIV-1 does not appear in the plasma until approximately 2-5 weeks after transmission, and neutralizing antibodies to autologous HIV-1 generally do not become detectable until 12 weeks or more after transmission. Moreover, levels of HIV-1-specific antibodies decline on antiretroviral treatment. The mechanisms of this delay in the appearance of anti-HIV-1 antibodies and of their subsequent rapid decline are not known. While the effect of HIV-1 on depletion of gut CD4(+) T cells in acute HIV-1 infection is well described, the authors studied blood and tissue B cells soon after infection to determine the effect of early HIV-1 on these cells. In human participants, they analyzed B cells in blood as early as 17 days after HIV-1 infection, and in terminal ileum inductive and effector microenvironments beginning at 47 days after infection. They found that HIV-1 infection rapidly induced polyclonal activation and terminal differentiation of B cells in blood and in gut-associated lymphoid tissue (GALT) B cells. The specificities of antibodies produced by GALT memory B cells in acute HIV-1 infection (AHI) included not only HIV-1-specific antibodies, but also influenza-specific and autoreactive antibodies, indicating very early onset of HIV-1-induced polyclonal B cell activation. Follicular damage or germinal centre loss in terminal ileum Peyer’s patches was seen with 88% of follicles exhibiting B or T cell apoptosis and follicular lysis. Early induction of polyclonal B cell differentiation, coupled with follicular damage and germinal centre loss soon after HIV-1 infection, may explain both the high rate of decline in HIV-1-induced antibody responses and the delay in plasma antibody responses to HIV-1.

Editors’ note: B lymphocytes are born and mature in the bone marrow before they enter the blood stream looking for interesting antigens. Once activated, they change into antibody-secreting cells and memory B lymphocytes that respond quickly to that antigen. The death of infected and uninfected CD4 T cells in the gut in acute infection is well known but less is understood about what happens to B cells and why the antibody response to HIV is so slow. This study demonstrates that Peyer’s patch B cells in the gut die massively, with significant germinal centre destruction. How this happens is unclear but we really need to understand how HIV subverts our initial humoral responses in order to know how quickly neutralising antibodies that are pre-primed by a vaccine would have to appear in order to be effective against HIV.