Gut-associated lymphoid tissue (GALT) is an important site for early HIV replication and severe CD4+ T-cell depletion. Initiation of highly active antiretroviral therapy leads to incomplete suppression of viral replication and substantially delayed and only partial restoration of CD4+ T cells in GALT compared with peripheral blood. Persistent viral replication in GALT leads to replenishment and maintenance of viral reservoirs. Increased levels of inflammation, immune activation, and decreased levels of mucosal repair and regeneration contribute to enteropathy. Assessment of gut mucosal immune system will provide better insights into the efficacy of highly active antiretroviral therapy in immune restoration and suppression of viral reservoirs.