Gut homing CD4+ T cells expressing the integrin 47 are early viral targets and contribute to HIV-1 pathogenesis, likely by seeding the gastrointestinal (GI) tract with HIV. Although simianized anti-47 monoclonal antibodies have shown promise in preventing or attenuating the disease course of simian immunodeficiency virus in nonhuman primate studies, the mechanisms of drug action remain elusive. We present a cohort of individuals with mild inflammatory bowel disease and concomitant HIV-1 infection receiving anti-47 treatment. By sampling the immune inductive and effector sites of the GI tract, we have discovered that anti-47 therapy led to a significant and unexpected attenuation of lymphoid aggregates, most notably in the terminal ileum. Given that lymphoid aggregates serve as important sanctuary sites for maintaining viral reservoirs, their attrition by anti-47 therapy has important implications for HIV-1 therapeutics and eradication efforts and defines a rational basis for the use of anti-47 therapy in HIV-1 infection.