Lymph nodes (LNs) represent the principal site where antigen-specific memory T- and B-cell responses are primed and differentiated into memory and effector cells. During chronic viral infections such as HIV, these lymphoid tissues undergo substantial structural changes. These changes are mostly caused by an imbalanced cytokine milieu, hyper-immune activation and collagen deposition leading to fibrotic LNs. The structural integrity of the LNs is essential to prime and maintain memory responses. Because cellular signalling events both up- and down-stream of FOXO3a are critical to the generation and the maintenance of lymphocyte memory, this review will focus on the interplay between the deregulation of the immune system caused by the virus and its impact on FOXO3a.