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Abstract
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, we studied blood and tissue B cells soon after infection to determine the effect of early HIV-1 on these cells. In human participants, we 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. We 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 center 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 center 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. Please see later in the article for Editors' Summary.
Highlights
human immunodeficiency virus (HIV)-1 infection is characterized by the death of both infected and uninfected CD4+ T cells, often resulting in extensive CD4+ T cell depletion in the gastrointestinal tract [1,2,3,4,5,6]
Since similar B cell–inductive microenvironment damage existed in acute HIV-1 infection (AHI) patients both on and not on antiretroviral treatment (ART), we combined all AHI patients into a single group for the analyses of terminal ileum using immunohistology and flow cytometry data
Analysis We evaluated the status of B cells in acute HIV-1 infection in effector areas in situ in terminal ileum using immunohistochemistry
Summary
HIV-1 infection is characterized by the death of both infected and uninfected CD4+ T cells, often resulting in extensive CD4+ T cell depletion in the gastrointestinal tract [1,2,3,4,5,6]. The earliest B cell responses to HIV-1 are not detected until ,19 d after transmission in the form of antibody–virion immune complexes, and ,2–5 wk after transmission in the form of HIV-1 antibodies in plasma [18]. Functionally relevant neutralizing antibodies against autologous virus do not generally appear in plasma until $12 wk after HIV-1 infection [19,20,21]. 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. 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. HIV infects and kills a type of immune system cell called CD4+ T lymphocytes. The first antibodies to HIV usually appear two to seven weeks after infection; from about 12 weeks after infection, antibodies are made that can kill the specific HIV type responsible for the infection (neutralizing antibodies)
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