Two connected self-perpetuating cycles of inflammation, lymphoid tissue fibrosis, and immunodeficiency might be central to pathogenesis of antiretroviral untreated and treated HIV infection. Systemically, HIV-mediated increases in inflammation results in T-cell homeostasis, immunodeficiency, increased pathogen burden, and more inflammation (A). Within the local lymphoid tissues, HIV-associated CD4⁺ T-cell loss results in reduced production of lymphotoxin-beta, which is essential in maintaining the architecture necessary to produce new T cells (B). Professional illustration by Paulette Dennis.