Identifying physiological tissue niches that support the HIV reservoir in T cells

Successful antiretroviral therapy (ART) can efficiently suppress Human Immunodeficiency Virus-1 (HIV-1) replication to undetectable levels, but rare populations of infected memory CD4⁺ T cells continue to persist, complicating viral eradication efforts. Memory T cells utilize distinct homing and adhesion molecules to enter, exit, or establish residence at diverse tissue sites, integrating cellular and environmental cues that maintain homeostasis and life-long protection against pathogens. Critical roles for T cell receptor and cytokine signals driving clonal expansion and memory generation during immunity generation are well established, but whether HIV-infected T cells can utilize similar mechanisms for their own long-term survival is unclear. How infected, but transcriptionally silent T cells maintain their recirculation potential through blood and peripheral tissues, or whether they acquire new capabilities to establish unique peripheral tissue niches, is also not well understood. In this review, we will discuss the cellular and molecular cues that are important for memory T cell homeostasis and highlight opportunities for HIV to hijack normal immunological processes to establish long-term viral persistence.