(A) The intact intestinal epithelium in uninfected individuals. Commensal bacteria and released microbial products, including LPS, are restricted to the gut lumen by a continuous lining of enterocytes. (B) Translocation of commensal bacteria and bacterial products from the gut lumen into the intestinal wall and peripheral blood during HIV-1 infection. HIV-1 infection induces death of intestinal epithelial cells and depletes intestinal CD4⁺ T cells, particularly Th17 cells. Loss of intestinal epithelial cells allows commensal bacteria to enter intestinal wall. Loss of Th17 cells allows bacterial overgrowth. Translocation of microbial products into peripheral blood causes systemic immune activation. Activated peripheral CD4⁺ T cells are highly susceptible to HIV-1 infection. (C) The drug sevelamer blocks translocation of bacterial LPS into the systemic circulation, preventing immune activation. Sevelamer binds and sequesters bacterial LPS in intestinal lumen. Blocking bacterial LPS translocation of LPS into the circulation prevents systemic immune activation, leaving the majority of peripheral CD4⁺ T cells quiescent and unsusceptible to HIV-1 infection.