Although white AT can contribute to anti-infectious immune responses, it can alsobe targeted and perturbed by pathogens. The AT’s immune involvement is primarilydue to strong pro-inflammatory responses (with both local and paracrine effects),and the large number of fat-resident macrophages. Adipocytes also exert directantimicrobial responses. In recent years, it has been found that memory T cellsaccumulate in AT, where they provide efficient secondary responses against viralpathogens. These observations have prompted researchers to re-evaluate the linksbetween obesity and susceptibility to infections. In contrast, AT serves as a reservoirfor several persistence pathogens, such as human adenovirus Ad-36,Trypanosomagondii,Mycobacterium tuberculosis, influenza A virus, and cytomegalovirus (CMV). Thepresence and persistence of bacterial DNA in AT has led to the concept of a tissue-specific microbiota. The unexpected coexistence of immune cells and pathogens withinthe specific AT environment is intriguing, and its impact on anti-infectious immuneresponses requires further evaluation. AT has been recently identified as a site ofHIV persistence. In the context of HIV infection, AT is targeted by both the virusand the antiretroviral drugs. AT’s intrinsic metabolic features, large overall mass, andwide distribution make it a major tissue reservoir, and one that may contribute to thepathophysiology of chronic HIV infections. Here, we review the immune, metabolic, viral,and pharmacological aspects that contribute to HIV persistence in AT. We also evaluatethe respective impacts of both intrinsic and HIV-induced factors on AT’s involvement asa viral reservoir. Lastly, we examine the potential consequences of HIV persistence onthe metabolic and immune activities of AT.