HIV infection still represents a pandemic in 2024. Despite effective antiretroviral therapy (ART), the virus persists, forming latent HIV reservoirs in long-lived memory CD4+ T cells. Reservoirs exist in anatomical compartments like blood, lymphoid tissues, and the gut. Studies on HIV-infected cells in the blood have identified cellular markers preferentially expressed by these cells. Most research focuses on peripheral blood, representing <2% of total CD4+ T cells, emphasizing the need to explore tissues. The gut represents a major reservoir site, housing most of HIV-infected cells. Considering the distinct cellular composition of the gut in comparison to the blood we hypothesize that latently infected cells from the gut may exhibit a preferential expression of markers that differ from those observed in the blood. Moreover, we think that the microenvironment of the gut may favor the long-term persistence of latent HIV. Combining transcriptomic and proteomic analyses of HIV-infected gut explants and biopsies from people-living-with-HIV, we will obtain unique insights into the factors that determine HIV latency in the gut. Specific markers of latency that we identify in this study might instigate novel therapeutic approaches aimed at eliminating HIV reservoirs in the gut.