Despite suppression of human immunodeficiency virus (HIV) replication by antiretroviral therapy, reconstitution of CD4⁺ cells is variable and incomplete, particularly in gut-associated lymphatic tissues (GALT). We have previously shown that immune activation and inflammation in HIV-infected and simian immunodeficiency virus-infected lymph nodes results in collagen deposition and disruption of the lymphatic tissue architecture, and this damage contributes to CD4⁺ cell depletion before treatment and affects the extent of immune reconstitution after treatment. In the present study, we compared collagen deposition and the extent of depletion and reconstitution of total CD4⁺ cells and subsets in peripheral blood, lymph nodes, and inductive and effector sites in GALT. We show that CD4⁺ cell depletion in GALT correlates with the rapidity and greater magnitude of collagen deposition in this compartment, compared with that in peripheral lymph nodes, and that although treatment does not restore CD4⁺ cells to effector sites, treatment in the early stages of infection can increase CD4⁺ central memory cells in Peyer patches.