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.
Purpose of review People with HIV (PWH) are increasingly susceptible to excess weight gain and obesity after initiation of antiretroviral therapy. However, there is substantial variation in individual weight gain that is difficult to predict with clinical factors alone. We review emerging methods in machine learning and multi-omics that address the biology and prediction of weight gain and weight-associated conditions, persistent challenges, and future directions. Recent findings PWH continue to have increasing burden of excess weight gain and obesity. Obesity has a complex pathophysiology with an interplay between biological and environmental factors that make weight gain prediction challenging. Few studies in PWH have used omics or machine learning to capture weight gain trajectories. These studies highlight the promise and challenges of leveraging multi-omics and machine learning for modeling weight gain. Summary Advances in machine learning and scalable multi-omics have accelerated research defining pathways of human health and disease. These tools may have an important role in defining the biology and predictors of weight gain in PWH, ultimately to improve risk stratification and identify targeted interventions to improve health outcomes in PWH.
PURPOSE OF REVIEW:People with HIV (PWH) require lifelong antiretroviral therapy (ART) to maintain viral suppression, yet integrated HIV DNA persists in long-lived cellular reservoirs in blood and tissues. Most integrated proviruses are defective, meaning they contain deletions, hypermutation, packaging-signal defects, splice defects, or other defects that prevent production of replication-competent viruses. However, these genomes are not necessarily biologically inert as many remain capable of transcription and, in some cases, translation of viral proteins. RECENT FINDINGS:Recent evidence has demonstrated that the brain is a stable reservoir of both intact and defective HIV despite viral suppression with ART. Whilst intact replication capable proviruses are known to induce cell activation and pathology, recent studies suggest that defective proviruses with large internal deletions and hypermutation can remain transcriptionally, and in some cases, translationally active and have now been linked with persistent immune activation during ART. Therefore, transcriptionally active defective proviral DNA may be a contributor to underlying neuropathogenesis in ART-suppressed PWH. SUMMARY:Defective HIV proviruses make up the majority of the proviral reservoir across blood and tissue compartments. Although they are replication-incompetent, many remain transcriptionally and translationally competent and may contribute to chronic inflammation, antigen persistence, and neuropathology in ART-suppressed PWH.
PURPOSE OF REVIEW:Neurocognitive disorders and neuropathology continue to affect a subset of people with HIV (PWH) despite long-term viral suppression with antiretroviral therapy (ART). The mechanisms driving persistent neuropathology remain incompletely defined, and current therapeutic options are largely nonspecific and patient-dependent. This review analyses emerging evidence on HIV-associated neuropathology in ART-suppressed PWH, with a particular focus on the role of the gut-brain axis. RECENT FINDINGS:Recent studies demonstrate that the CNS is a stable and transcriptionally active tissue reservoir, which may sustain chronic microglial activation, pro-inflammatory signalling, and synaptic injury. In parallel, accumulating evidence implicates systemic inflammation and gut barrier dysfunction as key contributors to neuroinflammation, linking microbial translocation and gut-brain axis perturbations to cognitive decline in PWH. Furthermore, persistent gut inflammation may result in enteric nervous system (ENS) dysfunction and aberrant signals that directly results in neuroinflammation and neuropathology. These mechanistic insights have driven evaluation of adjunctive strategies targeting HIV transcription and inflammatory pathways as potential approaches to limit neuropathogenesis. SUMMARY:Neuropathology in ART-suppressed PWH arises from convergent processes involving CNS HIV reservoirs, myeloid-driven neuroinflammation, systemic immune activation and gut-derived injury, rather than residual brain infection alone. Defining the relative contribution of these pathways in PWH and developing CNS-penetrant interventions that silence viral transcription, restore gut integrity and dampen systemic inflammation, will be critical to preventing and treating HIV-associated neuropathology.
PURPOSE OF REVIEW:People with HIV (PWH) on effective antiretroviral therapy continue to experience a disproportionate burden of age-related comorbidities and multimorbidity. This review explores HIV-associated aging as a systems-level dysregulation and loss of resilience and evaluates emerging biomarker strategies for capturing its biological and clinical heterogeneity. RECENT FINDINGS:Recent evidence indicates that aging in HIV is driven by interacting immune, metabolic, regenerative, structural, and inter-organ pathways that generate measurable signatures across biological scales. Composite biomarker approaches integrating molecular, physiological, and functional measures are increasingly being applied to cardiovascular, neurocognitive, physical, and co-infection-related outcomes. Large cohort studies, risk prediction models, and intervention trials support their clinical relevance, while emerging gerotherapeutic studies suggest that biologic aging markers may serve as responsive treatment endpoints. SUMMARY:No single biomarker adequately captures HIV-associated aging. Future progress will depend on multimodal, outcome-anchored composites that integrate biological and functional domains and are coupled with artificial intelligence- and machine learning-based approaches to improve risk stratification, therapeutic monitoring, and evaluation of geroscience-informed interventions in PWH.
PURPOSE OF REVIEW:The increasing use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for type 2 diabetes and obesity has generated interest in their potential role among people with HIV (PWH), who experience a high burden of cardiometabolic disease and aging-related comorbidities. This review summarizes emerging evidence on the efficacy, safety, and implementation considerations of GLP-1RAs in PWH. RECENT FINDINGS:GLP-1RAs, such as semaglutide, are associated with meaningful reductions in bodyweight, glycemia, and both visceral and hepatic fat in PWH. Emerging data suggest potential effects on behavioral outcomes such as alcohol use and smoking, although evidence in PWH remains limited. Concerns regarding lean mass loss, frailty, and bone health exist but current data are limited and generally reassuring, with functional outcomes largely preserved. HIV-specific studies have largely used lower doses of semaglutide, and evidence in older populations remains sparse. SUMMARY:GLP-1RAs are a promising option for cardiometabolic risk reduction in PWH, with important considerations around tolerability and body composition, particularly in aging and multimorbid populations. Future research should prioritize trials assessing cardiovascular, neuropsychiatric, and substance use outcomes, alongside studies of real-world effectiveness and implementation in routine clinical care. In addition, identifying subgroups most likely to benefit will be important.
PURPOSE OF THE REVIEW:This review summarizes recent advances in understanding HIV infection of the brain, focusing on viral persistence in microglia and associated pathogenesis during viremia and viral suppression. We highlight key findings in microglial research that inform the next steps toward therapeutic strategies and cure approaches addressing the brain as a viral reservoir. RECENT FINDINGS:Microglia can contain intact, replication-competent inducible proviruses, even during antiretroviral therapy (ART). The microglial chromatin context and HIV integration site landscape during HIV infection are reportedly distinct from peripheral lymphocytes. Upon infection, both infected and bystander microglia exhibit pro-inflammatory and senescent phenotypes that closely resemble those observed in aging microglia and play a central role in neuropathogenesis. ART mitigates these effects but does not fully restore to levels observed in HIV-uninfected conditions. SUMMARY:Microglial HIV infection and persistence of this reservoir play a central and detrimental role in HIV pathogenesis in the brain. Given their role in neurodegeneration during HIV infection, closer characterization of the microglial (latent) reservoir and careful monitoring of neurodegeneration during treatment and cure interventions are essential. Treatment and cure strategies should prioritize minimizing viral transcription and protein expression within the brain reservoir to mitigate neuroinflammation and neuropathogenesis.
Purpose of reviewOver the past few years, it has become increasingly clear that starting antiretroviral therapy (ART) during acute HIV infection (AHI) leads to a faster viral reservoir decay and partial preservation of the immune system. Here, we review the benefits of treating AHI for the reservoir composition and the adaptive immune function, as well as implications for HIV cure studies.Recent findingsAHI is most commonly defined as the first 6 months following infection. During this early infection stage of infection, HIV viremia reaches its peak, concurrently with the development of the HIV-specific immune response. Early ART limits the size of the viral reservoir, and a smaller reservoir is associated with of longer time to viral rebound posttreatment interruption and, in some cases, posttreatment control (PTC). Moreover, initiating ART during AHI partially preserves the function of T and B cells, leading to improved control of the viral reservoir, and potentially creating windows for HIV cure strategies.SummaryRecent cure studies show that both CD8+ T-cell and antibody responses provide important clues for predicting PTC, as individuals with robust, functional immune profiles are more likely to maintain viral suppression after stopping ART. However, while early ART initiation lowers the viral reservoir and preserves immune function, these factors alone are not sufficient for PTC, highlighting the need for a comprehensive molecular profile that integrates viral and host biomarkers to reliably predict PTC.
PURPOSE OF REVIEW:Perinatal HIV infection occurs during a critical window of immune development, in a predominantly naïve immune system, resulting in distinct and unique virologic and immunologic outcomes compared with adult-acquired infection. Innate immunity and specifically natural killer (NK) cells play a role in early viral control and critically shape both size and composition of the HIV reservoir established in infancy. This review examines how NK cell function during acute infection and treatment interruption may contribute to virological outcomes. RECENT FINDINGS:Emerging data show that NK cell phenotypic and functional diversity associates with reservoir size and persistence. Immune-genetic factors, including HLA and KIR interactions and sex-specific differences, can significantly modulate NK-mediated HIV control. Studies also highlight how perinatal HIV exposure and co-infections alter innate immune networks involving monocytes and CD8 T cells, further influencing reservoir dynamics. SUMMARY:Insights into pediatric NK cell immunity reveal unique mechanisms of early HIV control and reservoir shaping that differ from adults. Understanding how NK cell function influences virological outcomes during acute infection and analytic treatment interruption (ATI) provides a critical foundation for designing cure strategies tailored to children. These include leveraging antibody-based interventions and emerging NK-directed immunotherapies to enhance reservoir clearance and support safer, more effective ATI-informed cure approaches.
PURPOSE OF REVIEW:HIV cure research seeks to eradicate the virus from people with HIV (PWH) or provide posttreatment control (PTC) of virus sufficient to block new transmissions and provide better health outcomes. Nonhuman primate (NHP) models of HIV have proven instrumental to our understanding HIV infection. This review highlights the remarkable contributions of NHPs in both corroborating data from PWH and expanding our understanding beyond what is possible in a clinical setting by utilizing novel virus models, immune activating therapies, and direct in vivo intervention to clear the viral reservoir. RECENT FINDING:The benefits of NHP models for HIV cure research encompasses both basic research and a platform to test novel preclinical therapeutic interventions. Recent findings have improved our basic understanding of how and when the HIV reservoir is established, the mechanisms of how it is maintained, and the dynamics and origins of off-ART rebound. Further, NHP studies have allowed the testing of various intervention strategies, for both PTC and reservoir reduction, including interventions that can and are being tested in PWH as well as models that cannot be used in humans, but can provide mechanistic insights into reservoir dynamics that can help develop future clinical interventions. SUMMARY:NHP research has proven highly useful in all aspects of HIV disease. The exciting new virus models and intervention approaches described here have and will continue to meaningfully contribute to the goal of HIV cure.
Stronger type I interferon responses in females compared to males, starting from intrauterine life, underpin the sex differences observed in HIV-1 cure/remission outcomes in children and adults. In adults these innate immune sex differences favour females achieving HIV-1 cure/remission over males. Recent studies of the adult viral reservoir reflect the ability of innate immune responses in females, including natural killer (NK) cell activity, to remove cells harbouring intact proviral DNA more effectively than males. In children, the situation is more complex. Initially, in the first years of life, males have a higher propensity to achieve HIV-1 cure/remission, at this stage benefiting from the effects of having weaker interferon (IFN)-I responses, including low baseline HIV-1 DNA loads and being recipients of an IFN-I sensitive transmitted founder virus. By mid-childhood, the picture is mixed, with the impact of stronger innate immunity in females combined with the development of more effective HIV-specific CD8 + T-cell response via immune ontogeny tending to favour females beyond the age of 5-10 years. In children, therefore, the double-edged sword effects of IFN-I in the setting of vertical transmission and immune ontogeny results in distinct, dynamic sex advantages through childhood.
PURPOSE OF REVIEW:HIV integration into BACH2 is significantly enriched in people living with HIV (PLWH), but not in vitro . Specifically, HIV integration sites are enriched in the same orientation and upstream of BACH2 translation. HIV drives high levels of BACH2 expression through HIV-to- BACH2 splicing. BACH2, a transcription repressor that competes with AP-1 binding, is an effector-to-memory switch that restrains effector function, drives T cell stemness, and promotes long-lived memory. RECENT FINDINGS:Retroviral infection mouse model containing retroviral splice sites recapitulated the orientation- and site-dependent enrichment of integration into BACH2 , revealing in-vivo selection pressure favoring BACH2 expression. Two back-to-back BACH2 studies revealed that BACH2 promotes HIV persistence. High BACH2 activity in the gut tissue resident memory CD4 + T cells (T RM ) drives long-lived persistence of HIV-infected cells in the gut, while high BACH2 activity in the gut HIV-specific CD8 + T RM restrains effector function. Higher BACH2 activity in tissues than blood drives distinct mechanisms of HIV persistence in the gut versus blood. Finally, three back-to-back BACH2 studies revealed how druggable finetuning of BACH2 promotes chimeric antigen receptor (CAR)-T cell persistence and efficacy. SUMMARY:BACH2 promotes the persistence of both HIV and CAR-T cells by driving T cell stemness and long-lived memory.
PURPOSE OF REVIEW:An estimated 1.4 million children live with HIV-1, yet major gaps remain in understanding neonatal pathogenesis and curative strategies. Nonhuman primate (NHP) infant and mother-infant models provide a critical platform to investigate immune development, elucidate age-specific mechanisms of infection, and evaluate treatment responses, aspects that cannot be directly studied in humans. RECENT FINDINGS:Newborn macaques exhibit exaggerated gut and lymph nodes seeding, absent interferon-I responses, and accelerated progression compared to juveniles, while ultra-early antiretroviral treatment (ART, day 3) achieves 80% postanalytical treatment interruption (ATI) control that collapses by day 5 due to rapid reservoir fixation. Immunotherapies reveal mechanistic constraints: interleukin-15 agonists paradoxically prolong infected cell survival, whereas CD4-mimetics and BCL-2 inhibitors reduce proviral loads. Germline-targeting SOSIP vaccines elicit superior broadly neutralizing antibodies (bNAb) precursors in infants versus adults, though maternal antibody transfer remains inefficient. Neonatal AAV-delivered bNAbs exploit immune tolerance to confer multiyear protection against SHIV challenges. SUMMARY:NHP models, via timed infections, longitudinal and multitissue sampling, and safe ATI, dissect therapeutic windows guiding clinical translation. Advancing mother-infant NHP research is therefore essential to support the development of pediatric strategies for ART-free remission, a goal that remains challenging to achieve.
PURPOSE OF REVIEW:Broadly neutralizing monoclonal antibodies (bNAbs) represent a transformative frontier for the prevention, treatment, and potential remission of HIV in children. Given that over 95% of the pediatric population living with or at risk for HIV resides in low-income and middle-income countries (LMICs), prioritizing trials and implementation in these regions is an ethical and clinical imperative. This review identifies the primary structural, biological, and regulatory barriers that must be addressed to ensure equitable global access to bNAb-based interventions. RECENT FINDINGS:Recent trials in Africa suggest that dual-bNAb combinations can maintain viral suppression in children during ART interruptions and restrict the viral reservoir. While the lower weight-based dosing requirements in neonates and infants present a cost-effective advantage for pediatric HIV management, several scientific and implementation challenges persist. Biological barriers, such as substantial pre-existing resistance to specific bNAbs within HIV-1 Clade C isolates, necessitate region-specific combination therapies, which in turn increase manufacturing and programmatic complexity. Furthermore, pharmacokinetic modeling indicates that elevated viral loads accelerate bNAb clearance, directly influencing optimal dosing strategies and highlighting a critical implementation gap in settings with limited viral load monitoring. Current trials in children are notably behind those in adults, with a lack of confirmatory efficacy data. These biological and clinical challenges are further limited by operational challenges, including climate-driven issues and infrastructure deficits that threaten the cold-chain logistics essential for biologic distribution, posing significant barriers to equitable global access. SUMMARY:While bNAbs offer a promising path toward HIV remission and simplified prevention, their success in LMICs depends on overcoming specific implementation barriers. Addressing these challenges is essential to prevent a delayed and inequitable deployment of these therapies to children in need. All stakeholders within the process from discovery to final implementation need to be involved for an appropriate implementation.
PURPOSE OF REVIEW:Sustained antiretroviral therapy (ART)-free HIV remission has been observed in a few early-treated children, highlighting the potential for pediatric HIV cure strategies. However, the risks associated with analytical treatment interruption (ATI) underscore the need for reliable virological biomarkers that can identify participants for ATI studies, predict viral rebound or remission and guide clinical decision-making. This review summarizes evidence on virological biomarkers of HIV remission with relevance to pediatric populations. RECENT FINDINGS:Advances in reservoir measurement have revealed that early ART initiation in children restricts reservoir size and alters reservoir quality. Total and intact HIV DNA, cell-associated HIV RNA, residual plasma viremia measured by ultrasensitive assays, and viral genetic and clonal features each capture aspects of HIV persistence and show associations with time to viral rebound. Markers of residual viral activity, including cell-associated HIV RNA, ultrasensitive plasma HIV RNA, and p24 antigen, may be predictors of rebound timing in early-treated cohorts. SUMMARY:Current evidence supports integrated, multi-dimensional virological biomarker strategies rather than reliance on single assays to predict pediatric HIV remission. Harmonization, validation in longitudinal pediatric cohorts, ethical feasibility and further research will be critical to identifying and translating these biomarkers for pediatric cure trials.
