Background People with HIV (PWH) are at increased risk for non-AIDS comorbidities despite suppressive ART. Chronic co-infections with CMV and EBV may contribute to systemic immune activation and comorbidities, but the relative contribution of viral activity vs host immune response is unclear.Methods We evaluated associations between viral measures and the Veterans Aging Cohort Study (VACS) Index 2.0, a validated 5-year mortality risk score for PWH. Plasma CMV and EBV IgG were quantified by ELISA, and CMV, EBV, and HIV cell-associated DNA (CA-DNA) were measured in peripheral blood mononuclear cells by droplet digital PCR. Total globulin levels were abstracted from clinical panels as a marker of generalized immune activation. Regression models were adjusted for sex, race, ethnicity, HIV duration, and history of AIDS.Results Among 485 ART-suppressed PWH (mean age 54 years; 17% women; 59% White), 96.5% were CMV seropositive, 100% EBV seropositive, CMV CA-DNA was detected in 45.9%, EBV in 95.4%, and HIV in 99.0%. Higher VACS scores were associated with higher CMV IgG, EBV IgG, EBV CA-DNA, HIV CA-DNA, and total globulin in adjusted models. In multivariable models, CMV IgG, EBV CA-DNA, and total globulins remained independently associated with VACS Index 2.0. HIV CA-DNA and sex were retained in the best-fit model with trend-level significance.Conclusions These findings suggest distinct mechanisms by which CMV, EBV, and HIV may contribute to morbidity in PWH on ART: CMV through immune activation, and EBV and HIV through viral persistence. Longitudinal studies are needed to clarify causal pathways and guide interventions. In people with HIV on virally suppressive ART, higher CMV IgG and EBV cell-associated DNA levels were associated with increased VACS Index 2.0 mortality risk scores, suggesting distinct mechanisms by which chronic herpesvirus co-infections may contribute to morbidity and mortality risk.

Introduction: End-of-life (EOL) HIV cure-related research offers a unique opportunity to advance scientific discovery while honoring the values, dignity, and legacy of people with HIV. However, participation remains demographically skewed, mirroring long-standing inequities in who is informed, invited, and supported to take part. Synthesizing eight years of experience, published literature reviews, and community engagement from the University of California San Diego’s Last Gift program, we propose strategies to embed justice, equity, diversity, inclusion, and accessibility (JEDIA) throughout the design and implementation of EOL HIV cure-related studies. Discussion: Using intersectionality as a structural analytic framework, we examine how interlocking systems and social determinants shape access, consent, and participant experience, and we translate ethics into action across three themes and eight domains. As examples, we facilitate equitable access by implementing solutions that address gaps limiting awareness and feasibility of participation. We establish ongoing consent through multi-session consent processes with teach-back methods, clear healthcare proxy pathways, and explicit separation of research activities from clinical care. We center lived experiences by partnering with people with HIV and community groups, customizing participation, and honoring cultural and spiritual needs. We enable real-time course correction by using a dashboard that monitors enrollment patterns and representation. Conclusions: An intersectionality-informed, participant-centered approach is both feasible and essential to ensure HIV cure-related research advances with fairness, trust, and global relevance. Programs such as the Last Gift show that scientific rigor, integrity, and participant dignity can coexist, establishing a model for equitable HIV cure discovery.

BACKGROUND:People with HIV (PWH) remain at risk for cognitive impairment, despite effective antiretroviral therapy (ART), a phenomenon linked to chronic immune activation and inflammation. Cytomegalovirus (CMV) has been implicated in HIV-associated neurocognitive impairment, but most studies rely on serologic measures that may not capture biologically relevant viral-host interactions. Few studies have examined cell-associated CMV markers or evaluated sex-specific associations with cognition. METHODS:We conducted a retrospective cross-sectional analysis of 485 PWH on suppressive ART (HIV RNA<200 copies/ml). Cognitive performance was assessed globally and across seven domains. Cell-associated CMV, Epstein-Barr virus (EBV), and HIV cell-associated DNA in peripheral blood mononuclear cells (PBMCs) were quantified by ddPCR, and CMV and EBV immunoglobulin G (IgG) levels were measured by ELISA. Multivariable linear regression models adjusted for demographic and clinical covariates were used to assess associations with cognitive performance, including evaluation of sex interactions, with false discovery rate correction applied. RESULTS:In adjusted models, lower cell-associated CMV DNA, but not CMV IgG, EBV markers, or HIV DNA, was associated with poorer working memory and global cognitive performance. Significant interactions between CMV DNA and sex were observed for global, executive function, processing speed, and memory. In sex-stratified analyses, these associations were present among women but not in men. CONCLUSIONS:Cell-associated CMV DNA demonstrates sex-modified associations with cognitive performance among ART-suppressed PWH, with effects observed primarily in women. These findings, based on cellular rather than serologic CMV measures, underscore the complexity of host-virus interactions and cautions against interpreting cell-associated CMV DNA as a simple proxy for pathogenic viral activity.

Renato Bobadilla,1 Finn MacLean,2 Shravan Dave,3 Jason T Blackard,4 Sara Gianella1 1Division of Infectious Diseases and Global Public Health, University of California San Diego, La Jolla, San Diego, CA, USA; 2Medical Scientist Training Program, University of California San Diego, La Jolla, San Diego, CA, USA; 3Division of Gastroenterology and Hepatology, University of California San Diego, La Jolla, San Diego, CA, USA; 4Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USACorrespondence: Sara Gianella, Division of Infectious Diseases and Global Public Health, University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093, USA, Email gianella@health.ucsd.edu

HIV-1 persists in CD4⁺ T cells and brain microglia through host factors that enforce viral latency, yet the mechanisms that stabilize key transcriptional regulators remain incompletely understood. Here, we identify the YEATS domain-containing protein ENL and its associated deubiquitinase USP7 as a host complex that maintains HIV-1 latency. USP7 stabilizes BRD4 by deubiquitination, suppressing HIV transcription and sustaining viral quiescence. Disruption of the ENL-USP7 complex using selective PROTACs reactivates latent HIV in cell line models, as well as in resting CD4⁺ T cells and microglia isolated from people with HIV on antiretroviral therapy. These findings uncover a critical ENL-USP7-BRD4 axis that enforces HIV-1 latency and highlight USP7 as a potential target for latency-reversing strategies. Highlights:ENL, a YEATS domain-containing crotonylation reader, acts as a suppressor rather than an activator of HIV-1 transcription.ENL recruits USP7 to stabilize BRD4 and enforce viral latency.Disruption of the ENL-USP7-BRD4 axis reactivates latent HIV in T cells and microglia.Targeting USP7 or ENL reveals a therapeutic vulnerability in HIV reservoirs.

Despite transformative advances in antiretroviral therapy, human immunodeficiency virus (HIV) remains a lifelong condition driven by durable viral reservoirs, chronic immune dysfunction, and complex interactions with host biology, coinfections, and aging. While implementation science is essential to ensure that effective interventions reach populations most affected by HIV, implementation cannot succeed in isolation from continued discovery or from the political and social contexts in which care is delivered. This editorial highlights critical gaps in our understanding of sex-based immunologic differences, tissue-specific viral persistence, resistance evolution, and the long-term inflammatory and metabolic consequences of treated HIV-gaps that directly constrain the durability, equity, and scalability of prevention, treatment, and cure strategies. We further emphasize that successful translation depends on stable policy environments, sustained public investment, and trust-based partnerships with affected communities, without which even highly effective biomedical advances fail to achieve impact. Sustained investment across the full translational spectrum-from basic and mechanistic science through clinical, behavioral, and implementation research-is therefore essential. HIV research has repeatedly served as a model system driving advances across immunology, vaccinology, oncology, aging, and pandemic preparedness, underscoring its broader relevance to human infectious diseases.

BACKGROUND:People with HIV (PWH) are at increased risk for non-AIDS comorbidities despite suppressive antiretroviral therapy (ART). Chronic co-infections with Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) may contribute to systemic immune activation and comorbidities, but the relative contribution of viral activity versus host immune response is unclear. METHODS:We evaluated associations between viral measures and the Veterans Aging Cohort Study (VACS) Index 2.0, a validated 5-year mortality risk score for PWH. Plasma CMV and EBV IgG were quantified by ELISA, and CMV, EBV, and HIV cell-associated DNA (CA-DNA) was measured in peripheral blood mononuclear cells by ddPCR. Total globulin levels were abstracted from clinical panels as a marker of generalized immune activation. Regression models were adjusted for sex, race, ethnicity, HIV duration, and history of AIDS. RESULTS:Among 485 ART-suppressed PWH (mean age 54 years; 17% women; 59% White), 96.5% were CMV-seropositive, 100% EBV-seropositive, CMV CA-DNA was detected in 45.9%, EBV in 95.4%, and HIV in 99.0%. Higher VACS scores were associated with higher CMV IgG, EBV IgG, EBV CA-DNA, HIV CA-DNA, and total globulin in adjusted models. In multivariable models, CMV IgG, EBV CA-DNA, and total globulins remained independently associated with VACS 2.0. HIV CA-DNA and sex were retained in the best-fit model with trend level significance. CONCLUSION:These findings suggest distinct mechanisms by which CMV, EBV and HIV may contribute to morbidity in PWH on ART: CMV through immune activation, and EBV and HIV through viral persistence. Longitudinal studies are needed to clarify causal pathways and guide interventions.

This piece represents part of an ongoing exchange that began with a personal perspective and the thoughtful responses it generated within our community. Moments of challenge can create opportunities for recognition, connection, and collective care. While we cannot always remove the sources of pain, we can meaningfully shape how they are experienced by ensuring that no one carries them alone. Guided by the idea that presence and validation are powerful forms of support, this exchange seeks to foster mutual recognition and affirm experiences that are too often minimized or overlooked. By creating space for shared acknowledgment and listening, it emphasizes solidarity over isolation and connection over silence. If this dialogue helps individuals feel seen, supported, and less alone, it affirms the enduring power of community and shared humanity.

BACKGROUND:Alterations in the gut microbiome have been linked to chronic HIV infection, yet less is known about microbiome dynamics during the earliest phases of HIV acquisition. It remains unclear whether microbial changes precede or follow HIV infection, and whether specific taxa could serve as early biomarkers or modulators of disease progression. SETTING:The San Diego Primary Infection Resource Consortium, a large HIV resource infrastructure program that enrolled predominantly men who have sex with men in Southern California, USA. METHODS:We analyzed rectal swabs from 316 participants, 86 without HIV, 100 with acute (≤30 days postinfection), and 130 with early (31-180 days) untreated HIV infection. 16S rRNA sequencing was used to characterize bacterial communities. Alpha and beta diversity metrics and taxon-level relative abundance (RA) were compared across groups using generalized linear models and MaAsLin3, adjusting for confounders and correcting for false discovery rate (FDR). RESULTS:No significant differences in Shannon and Pielou index or beta diversity were observed by HIV status or stage. However, HIV infection was independently associated with a modest reduction in microbial richness (observed species; P = 0.039). Enterocloster clostridioformis was significantly depleted among people with HIV (aβ -1.31, FDR P < 0.001). Among participants with HIV, RA of Akkermansia muciniphila was positively correlated with plasma HIV RNA levels (aβ 0.48, FDR P = 0.016). CONCLUSION:The rectal bacteriome remains largely preserved during the first 6 months of untreated HIV infection. Subtle taxon-specific changes may reflect early viro-immunological perturbations but suggest limited diagnostic and prognostic utility of microbiome profiling.

HIV persistence within anatomical reservoirs remains the primary barrier to achieving an HIV cure. While antiretroviral therapy effectively suppresses plasma viremia, it does not eliminate integrated proviral genomes that persist in long-lived cellular compartments. The central nervous system (CNS) is a clinically important HIV reservoir, characterized by immune privilege and the persistence of tissue-resident infection despite effective antiretroviral therapy (ART). Evidence from postmortem studies reveals that HIV DNA, RNA, and even intact replication-competent proviruses remain detectable in brain tissue from virally suppressed people with HIV. Evidence derived primarily from in situ approaches and viable-cell studies supports myeloid-lineage reservoirs, particularly microglia and CNS-associated macrophages, as key cellular sources of persistence, while the extent and biological relevance of astrocyte infection remains debated. These reservoirs exhibit transcriptional activity and are associated with chronic neuroinflammation, which may contribute to HIV-associated neurocognitive disorders, despite systemic viral suppression. Here, we synthesize recent findings from autopsy brain studies, including work enabled by major biorepositories, such as the National NeuroHIV Tissue Consortium and rapid-autopsy programs, including the Last Gift, both of which are essential for studying HIV reservoirs in the CNS. We summarize methodologies for detecting and characterizing HIV in brain tissue, highlight heterogeneous patterns of regional distribution and compartmentalization, and review emerging links between CNS persistence and neuroinflammation. We conclude with priorities for harmonized tissue processing, multi-modal single-cell and spatial profiling, and coordinated cross-cohort analyses to clarify the contribution of CNS reservoirs to neuroHIV pathogenesis and systemic rebound.

After being told that my work was “not independent enough” and that I was “not doing real science,” I began to question how academic medicine defines success. Through teamwork in translational HIV-1 research and community-engaged programs like The Last Gift, I have come to see that independence is an illusion, and that collaboration, empathy, and connection are the true engines of discovery and impactful research. This reflection challenges the traditional, hegemonic, metrics of scientific achievement and calls for a broader definition that values mentorship, equity, and collective progress as essential to meaningful science.

Cytomegalovirus (CMV) infection is nearly universal among people with HIV (PWH) and contributes to chronic inflammation, immune senescence, and accelerated biological aging despite suppressive antiretroviral therapy (ART). This review summarizes recent advances in understanding the role of CMV in multimorbidity and aging in PWH, focusing on immune and tissue-based mechanisms, comorbidities, and emerging interventions. CMV reactivation drives clonal T-cell expansion, innate immune reprogramming, adipose tissue inflammation, metabolic rewiring, and durable cellular epigenetic changes that amplify risks for vascular disease, frailty, brain health disorders, diabetes mellitus, and cancer. Early interventional data indicate that letermovir can reduce inflammation and improve immune and frailty outcomes in PWH, while vaccines are advancing in clinical evaluation. CMV is a modifiable driver of immune dysfunction and aging in PWH. Targeted antiviral, vaccine, and host-directed approaches may reduce multimorbidity and promote healthy aging, particularly in populations at greatest risk. Cytomegalovirus (CMV) is nearly universal among people with HIV (PWH) and persists despite suppressive antiretroviral therapy (ART), driving chronic immune activation and accelerated biological aging. CMV is mechanistically linked to clonal T-cell expansion, innate immune reprogramming, metabolic rewiring, and durable epigenetic imprinting. Clinical consequences span multiple aging-related disorders, including frailty cardiovascular disease (CVD), cognitive decline, diabetes mellitus, and cancer. Therapeutic strategies under evaluation include anti-CMV drugs like letermovir and vaccines. Future directions emphasize precision, multimorbidity-focused interventions to extend healthspan in aging PWH.

HIV persistence is facilitated by immune evasion strategies that reshape host immune responses. As the Interferon Gamma (IFNG) gene encodes a key immunoregulatory cytokine whose transcriptional competence is governed by promoter CpG methylation, we hypothesized that HIV plasma RNA would track with epigenetic remodeling at the IFNG promoter, altering IFNG mRNA transcription. DNA methylation at the IFNG promoter was quantified by bisulfite sequencing in PBMCs from people with HIV (PWH) with high (n = 16; >5000 copies/µL), medium (n = 18; 500 to 4999 copies/µL), or undetectable (n = 18; ≤50 copies/µL) plasma HIV RNA. Corresponding IFNG mRNA was quantified by RT-qPCR, with a sensitivity analysis adjusting for T cell abundance. High detectable plasma HIV RNA was associated with significant IFNG hypomethylation across 4 out of 5 CpG sites in the IFNG promoter compared to those with medium HIV RNA, while those with undetectable plasma HIV RNA showed no significant differences after adjusting for duration of infection. Accordingly, IFNG mRNA transcription was significantly elevated in participants with high plasma HIV RNA compared to medium (p = 0.037), which strengthened after modeling TCF7 expression as a covariate to account for varying T cell counts (p = 0.02). These findings provide the first in vivo evidence correlating HIV viral load with epigenetic transcriptional control of IFNG in peripheral blood.

Background Female sex hormones used in feminizing hormone therapy (FHT) may influence activation and persistence of HIV pre-exposure prophylaxis (PrEP) medications. The clinical relevance of this interaction remains unclear, particularly for transgender and cisgender women (TGW and CGW). To address this gap, we examined drug metabolites in HIV susceptible cells isolated from blood and rectal tissues of TGW and CGW. Materials and Methods We enrolled 23 TGW, 13 on FHT and 10 CGW. Participants received five directly observed daily PrEP doses: emtricitabine 200 mg with either tenofovir disoproxil fumarate 300 mg (FTC/TDF) or tenofovir alafenamide 25 mg (FTC/TAF). Blood and rectal tissue samples were obtained. Mononuclear and CD4(+) cells were isolated and analysed for intracellular triphosphorylated nucleotides (TFVdp and FTCtp) and total nucleotide pools (pTFV and pFTC) using HPLC-MS/MS. Serum hormone concentrations were quantified via enzyme immunoassay. Results and Conclusion Total nucleotide pools (pTFV and pFTC) correlated with active metabolites (TFVdp and FTCtp) in blood and rectal CD4(+ )cells (r(2) > 0.75, p < .001). No significant differences in pTFV or pFTC concentrations were observed between high and low oestradiol groups in either CGW or TGW (p > .1). No correlation was observed between serum oestradiol concentrations and nucleotide concentrations. TAF resulted in 6.8-fold higher median pTFV concentrations in blood CD4(+) cells (p < .001) but eightfold lower median pTFV concentrations in rectal CD4(+) cells compared to TDF (p = .008). These findings suggest that neither endogenous hormonal fluctuations in CGW nor exogenous FHT in TGW adversely impact intracellular PrEP pharmacology in key HIV target cells.

In their reply to our Viewpoint, Schmitt and colleagues raise important considerations regarding safety and ethics in body donation. We share their commitment to program integrity but respectfully disagree with several aspects of their framing. Our initial viewpoint focused on body donation to medical schools for the specific education of physicians and other allied healthcare workers. Historical exclusion of donors with HIV, HBV, and HCV reflect outdated understandings of risk that no longer align with current science or infection-control standards. Characterizing health sciences students as a "vulnerable group" misconstrues both their training and the intent of bioethical protections, which were designed to ensure safety, not justify exclusion. Evidence demonstrates that with universal precautions, embalmed donors pose negligible infectious risk, and large-scale reliance on post-exposure prophylaxis is unwarranted. Inclusion of donors with well-controlled infections enhances education, equity, public trust, and fosters person-centered compassion. As one of the largest body donation programs in the U.S., the University of California is uniquely positioned to lead in modernizing donation policies that reflect evidence, ethics, and respect for all individuals who choose to contribute to science.

Despite effective antiretroviral therapy, HIV persists in the central nervous system (CNS) and may contribute to neuroinflammation and cognitive impairment. How viral persistence, immune responses, and regional CNS T-cell architecture relate to cognitive functioning remains unclear. We performed a cross-sectional, multi-compartmental immune-genomic study in 12 people with HIV on long-term viral suppression enrolled in the Last Gift rapid autopsy program. Quantitative HIV reservoir measures (total-episomal DNA, unspliced-multiply spliced RNA) and paired αβ T-cell receptor repertoire (TCRR) sequencing were performed in peripheral blood mononuclear cells and five CNS regions: hippocampus, frontal motor cortex, basal ganglia, occipital cortex, and spinal cord. Cognitive performance was assessed within one year of death. Tissue-resolved associations between cognition and HIV reservoir, TCRR architecture (richness, diversity, clonality), and pathogen-specific T-cell clonotypes (HIV, CMV, EBV, and riboflavin derivatives) were evaluated using participant-clustered multivariable models. False discovery rate was applied. HIV DNA and RNA were detectable across all tissues but were not associated with cognitive performance or TCRR metrics. Peripheral TCRR architecture was unrelated to cognition, whereas higher TCRR richness and diversity in the hippocampus and spinal cord were associated with worse verbal, motor, and attention/working memory scores. Higher TCRR richness in the spinal cord was also associated with better recall. T-cell receptor clonotype frequency distributions differed across CNS regions, consistent with regional immune compartmentalization. Epitope-inference analyses revealed pathogen-dependent associations: higher number of HIV-specific T-cell clonotypes in the basal ganglia was associated with better global and attention/working memory scores, whereas riboflavin derivative-specific clonotypes in frontal motor cortex were associated with better motor performance. CMV-specific clonotypes showed nominal associations with worse learning and memory. CNS-localized T-cell receptor architecture and antigenic imprinting related more closely to neurocognitive variability than quantitative measures of HIV persistence under viral suppression, highlighting regional specialization of T-cell responses as a potential correlate of brain health.

Sex hormones and reproductive transitions profoundly shape immune, metabolic, neuropsychological, and mucosal biology, as well as HIV persistence, across women's lives. Although women constitute the majority of people with HIV worldwide, hormonal and reproductive biology are still not sufficiently incorporated into HIV cure research. Cisgender women, transgender women on gender-affirming hormone therapy (GAHT), and gender-diverse individuals assigned female at birth are underrepresented in cure studies, despite experiencing unique and changing hormonal states that influence estrogen signaling, tissue-specific hormone exposure, and immune function. Estradiol, progesterone, and hormone-based therapies, including contraception, GAHT, and menopausal hormone therapy, influence innate and adaptive immunity, inflammatory responses, epithelial barrier function, and cardiometabolic and neurocognitive pathways. These processes also shape tissue-specific HIV reservoir formation and maintenance, modulate proviral transcription, and affect immune effector functions. However, most HIV cure strategies have been developed without systematically considering these hormone-dependent mechanisms, which limits mechanistic understanding, broad applicability, and translational relevance. In this review, we synthesize emerging evidence at the intersection of reproductive endocrinology and HIV immunovirology, identify critical knowledge gaps, and propose priorities for life-course, hormone-informed HIV cure strategies. We argue that meaningful inclusion of women and gender-diverse individuals is essential not only for ethically grounded, equity-centered, community-engaged research practices but also for the scientific rigor needed to achieve durable ART-free virologic control and cure.

BACKGROUND:End-of-life HIV research places emotional demands on staff, yet evidence for brief compassion training to enhance resilience is limited. OBJECTIVES:To assess the feasibility and impact of a four-week compassion training program on self-compassion and professional well-being. DESIGN:Prospective, single-group, repeated-measures pilot with surveys at baseline (T1), post-program (T2), and 12-week follow-up (T3). SETTING/PARTICIPANTS:Twenty-four professionals from the UC San Diego Last Gift program (83% women, 63% aged 25-44 years). MEASUREMENTS:Validated scales assessed self-compassion, compassion for others, professional quality of life, and work climate; changes were analyzed with Friedman and Bonferroni-adjusted Wilcoxon tests. RESULTS:Over-identification (p = 0.002), workplace joy (p = 0.005), and supportive work environment (p = 0.003) improved. Meditation frequency increased from T1 to T2 (p < 0.001) and remained higher at T3 (p = 0.006). CONCLUSIONS:A brief compassion program was feasible and improved over-identification and work-climate measures, supporting further evaluation of compassion support training in palliative and end-of-life research settings.