Purpose of review Tissue HIV-1 (HIV) reservoirs, particularly within the central nervous system (CNS), remain understudied because of limited access to well preserved human tissues. This review aims to highlight insights from rapid research autopsy studies into HIV persistence in the CNS, with a particular focus on viable-cell approaches, BMCs/microglia as cellular reservoirs, and the mechanisms underlying HIV latency and neuroinflammation. We also discuss key knowledge gaps and how these approaches may inform strategies to target CNS HIV reservoirs. Recent findings Recent rapid research autopsy studies demonstrate the value of combining tissue-based assays, viable CNS cell approaches, and advanced multiomics to investigate CNS HIV reservoirs, latency, viral–host interactions, and neuropathogenesis. Brain myeloid cells (BMCs)/microglia appear to be major CNS reservoirs that can harbor inducible, replication-competent HIV during suppressive ART, with latency regulated largely by epigenetic mechanisms. Persistent HIV transcription is associated with IFN-I signaling activation and neuroinflammation, potentially contributing to synaptic dysfunction and neuronal injury underlying HIV-associated neurocognitive disorders (HAND). Summary HIV persists in the CNS despite durable ART, with BMCs/microglia emerging as key reservoirs and potential targets for HIV cure strategies. The roles of CNS T cells, astrocytes, and pericytes as bona fide reservoirs remain to be established. Rapid-autopsy programs have enabled complementary tissue-based, viable-cell, phylogenetic, and multiomic approaches to resolve the complexity of CNS HIV persistence. Emerging evidence further links epigenetically regulated HIV latency and persistent IFN-I signaling to HIV reservoir maintenance and CNS injury. Future integration of viable-cell and spatial approaches with longitudinal clinical data will be critical for defining reservoir interactions and developing strategies to eliminate CNS HIV.
Purpose of review The review examines the how the HIV reservoir and its tissue distribution intersect with aging and comorbidity development in people with HIV (PWH) on suppressive antiretroviral therapy (ART) and considers implications for cure-directed research in an aging population. Recent findings PWH on ART carry a disproportionate and accelerating comorbidity burden, with multimorbidity projected to rise from 63 to 70% by 2030. Neurocognitive disorders, liver disease, lung disease, cardiovascular disease, and frailty are all elevated, and linked to the viral reservoir through chronic inflammation and direct viral mechanisms. Coinfections (HCV, HBV, CMV) compound this issue by amplifying the reservoir while independently driving the same comorbidities, particularly liver disease, and cardiovascular and frailty outcomes. Summary Reservoir persistence and comorbidity burden in aging PWH are mechanistically intertwined, with chronic inflammation as a common driver. These findings underscore the need for longitudinal, tissue-resolved studies spanning the lifespan, as well as inclusion of aged and comorbid individuals in cure-directed trials, given that immune-engagement-dependent cure strategies may exhibit differential efficacy in this growing population.
PURPOSE OF REVIEW:As people with HIV (PWH) age, obesity is increasingly prevalent, yet body weight alone inadequately captures the functional and metabolic consequences of adverse body composition remodeling. This review examines emerging evidence supporting a shift from weight-centric approaches toward a framework centered on sarcopenic obesity, muscle quality, and frailty in aging PWH. RECENT FINDINGS:Weight gain in the contemporary antiretroviral therapy era often reflects increased visceral and ectopic adiposity. Sarcopenic obesity is a clinically relevant phenotype characterized by the coexistence of excess adiposity and impaired muscle mass or function, with important implications for healthy aging. Emerging evidence highlights myosteatosis and impaired muscle quality as potential mechanistic links between adiposity and functional decline. Exercise-based interventions, particularly those incorporating resistance training, demonstrate promise for preserving physical function, reducing frailty, and improving body composition. In contrast, pharmacologic weight loss may raise concerns regarding lean tissue preservation if implemented without a concurrent focus on muscle health. SUMMARY:Obesity in aging PWH should be reframed as a body composition and functional health problem rather than simply excess body weight. Clinical and research priorities should emphasize early identification of vulnerability, preservation of muscle health, and interventions that support long-term physical resilience and independence.
PURPOSE OF REVIEW:This review highlights the rationale for and clinical experience in advancing age-specific adjuvantation systems to develop well tolerated and effective pediatric HIV vaccines. RECENT FINDINGS:Due to both cellular and soluble factors, infant immunity is distinct from that of older children and adults, featuring Th2 bias, tolerogenic APC programming, and reduced Tfh support. Due to distinct functional responses downstream of pattern recognition receptor signaling, adjuvant action is age-specific. Despite a growing pipeline of adjuvants and increasing interest in developing early-life immunization strategies against HIV, few adjuvants have been rigorously evaluated for use in pediatric HIV vaccines. In line with FDA Modernization Act 2.0, systems vaccinology and age-specific immunoprofiling in vivo and in vitro can inform down selection and optimization of age-specific adjuvanted HIV vaccine formulations. Several adjuvants have been assessed as components of HIV vaccines in infants including Alum, the oil-in-water emulsion MF59 and the TLR4 agonist glucopyranosyl lipid A (GLA). SUMMARY:There is strong rationale to develop an infant HIV vaccine to provide early-life protection, and several adjuvants have been assessed thus far in early-phase clinical studies. With a growing adjuvant pipeline, much work remains to assess which adjuvants should be advanced for an infant HIV vaccine. Leveraging age-specific preclinical studies including immune profiling and human in-vitro modeling can inform down selection to identify adjuvantation systems offering safety and antigen dose sparing, while enhancing breadth and durability of vaccine immunogenicity.
PURPOSE OF REVIEW:This review aims to deepen our appreciation of the intricate interactions underpinning CD8 + T-cell-mediated immunity to HIV-1, from the whole-cell level to the structure and function of signalling molecules driving diverse transcriptional programmes and differentiation states. RECENT FINDINGS:Unravelling the signals that trigger T-cell activation, elucidating the dynamic architecture of the immunological synapse, and comprehensive, high-resolution tissue cell atlases are transforming our understanding of T-cell biology during viral infections. SUMMARY:This review links multiple processes that together generate T-cell immunity with possible implications for vaccine development. It begins by examining the role of T-cell-mediated responses in protection against HIV-1 and the importance of targeting vulnerable epitopes on HIV-1 proteins to suppress viral replication. It then zooms in on the initiation of T-cell activation, differentiation, and effector functions, mediated by the formation of the immunological synapse, co-stimulatory signalling, and cytokine networks, which drive coordinated actions of multiple transcription factors and chromatin remodelling. It emphasizes the importance of T-cell diversity, the continuum of cellular differentiation states, tissue localization, and memory formation in shaping effective antiviral immunity.
