People with HIV are more likely to have opioid use disorder and to be prescribed opioids for chronic pain than the general population; however, the effects of opioids on the immune system and HIV persistence have not been fully elucidated. Opioids may affect HIV reservoirs during their establishment, maintenance, and reactivation by enhancing HIV infectivity and replication due to upregulation of co-receptors and impairment of innate antiviral responses. Opioids may also modulate immune cell functioning and microbial translocation and can reverse viral latency. In this review, we summarize the current findings for and against the modulating effects of opioids on HIV cellular and anatomical reservoirs, highlighting the current limitations that affect in vitro, ex vivo, and in vivo studies in the field. We propose further research targets and potential strategies to approach this topic.

Structural brain abnormalities, including those in white matter (WM), remain common in people with HIV (PWH). Their pathogenesis is uncertain and may reflect multiple etiologies. Oxidative stress is associated with inflammation, HIV, and its comorbidities. The post-translational carbonylation of proteins results from oxidative stress, and circulating protein carbonyls may reflect this. In this cross-sectional analysis, we evaluated the associations between protein carbonyls and a panel of soluble biomarkers of neuronal injury and inflammation in plasma (N = 45) and cerebrospinal fluid (CSF, n = 32) with structural brain MRI. The volume of abnormal WM was normalized for the total WM volume (nAWM). In this multisite project, all regression models were adjusted for the scanner. The candidate covariates included demographics, HIV disease characteristics, and comorbidities. Participants were PWH on virally suppressive antiretroviral therapy (ART) and were mostly white (64.4%) men (88.9%), with a mean age of 56.8 years. In unadjusted analyses, more nAWM was associated with higher plasma protein carbonyls (p = 0.002) and higher CCL2 (p = 0.045). In the adjusted regression models for nAWM, the association with plasma protein carbonyls remained significant (FDR p = 0.018). Protein carbonyls in plasma may be a valuable biomarker of oxidative stress and its associated adverse health effects, including within the central nervous system. If confirmed, these findings would support the hypothesis that reducing oxidative stress could treat or prevent WM injury in PWH.

Background/Objectives: End-of-life (EOL) HIV cure research, which studies HIV persistence through pre- and post-mortem tissue collection, has focused primarily on people living with HIV (PLWH) with a prognosis of six months or less. However, the perspectives of long-term survivors (LTS) diagnosed before the advent of effective antiretroviral treatment (ART) remain underexplored. Understanding their motivations and concerns about EOL cure research is essential for creating inclusive and ethical research frameworks. Methods: Between 2023 and 2024, we conducted in-depth qualitative interviews with 16 PLWH aged 60 and older from diverse backgrounds across the United States, recruited through community-based organizations and HIV networks. We used inductive thematic analysis to explore LTS’ perspectives on EOL HIV research. Results: Participants included cisgender men (56.25%) and women (43.75%) with diverse racial identities. While participants supported EOL HIV cure research, their willingness to participate varied, influenced by awareness, logistics, and ethical concerns. Altruism-motivated participation, but misconceptions about procedures and concerns over bodily integrity represented potential barriers. Some viewed blood draws and leukaphereses as routine, while others expressed hesitancy with biopsies and post-mortem tissue retrieval. HIV stigma, historical mistrust, and cultural beliefs also played a role in willingness to participate. LTS emphasized the need for decentralized research sites, travel support, and financial safeguards. Conclusions: To include LTS in EOL HIV cure research, a community-driven approach is needed, focusing on clear communication, ethical considerations, logistical support, and linkages to EOL care. Addressing misconceptions and building trust, particularly within groups traditionally underrepresented in research, is essential to expanding participation.

Background: The gastrointestinal (GI) tract is a major reservoir of HIV and home to the body's most diverse microbiome. However, the role of the gut bacteriome in modulating local HIV persistence remains uninvestigated. Methods: Leveraging rapid autopsy samples (n = 113) from 24 people with HIV in the Last Gift cohort, we performed 16S rRNA sequencing and quantified total HIV DNA and multiply spliced Tat/Rev RNA (droplet digital polymerase chain reaction) across 5 GI segments: duodenum, jejunum, ileum, colon, and rectum. Associations between the relative abundance of bacterial taxa and reservoir characteristics were analyzed via multivariable models. Results: HIV DNA levels were highest in the jejunum, intermediate in the duodenum and ileum, and lowest in the colon and rectum (P < .05 for all). HIV transcriptional activity was higher than expected relative to the reservoir size in the duodenum and ileum. Bacterial communities significantly differed in richness and composition across the segments (permutational multivariate analysis of variance, P = .002). Higher richness was associated with increased HIV transcriptional activity in the small bowel (ρ = 0.32, P = .015) and decreased activity in the large bowel (ρ = −0.41, P = .013). Segment-specific associations between taxa and HIV reservoir were observed: among these, short-chain fatty acid producers, mucin degraders, and bile acid metabolizers were consistently associated with reduced reservoir size and activity in the large bowel but with enhanced transcription in proximal segments. Sensitivity analyses by antibiotic exposure, cancer, and viral load confirmed robustness of findings. Conclusions: The gut bacteriome modulates HIV reservoir size and activity, and these effects vary along the GI tract. This regional specificity must be considered when designing bacteriome-based strategies to reduce HIV persistence and improve cure efforts.

Background: As people living with HIV (PWH) age, they face new challenges that can have a negative impact on their quality of life (QOL) and mental health. Setting: This study enrolled PWH at the end of life (EOL) who were actively engaged in cure-related research in Southern California, United States. EOL was defined as having a prognosis of 6 months or less to live. We examined the relationship between QOL, mental health, and research participation. Methods: Structured assessments were used to collect comprehensive data on QOL and mental health. Results: From 2017 to 2023, 35 PWH in their final stages of life who were actively engaged in cure-related research were enrolled. Their median age was 62.7 years, and most were White or otherwise non-Hispanic/non-Latino (90.6%), and male (86.7%). Changes in QOL and the presence of neurologic and psychiatric conditions, with a focus on depression and anxiety, were the primary outcomes assessed in this study. Participants had stable QOL scores throughout the study. There was an inverse relationship between QOL and Beck Depression Inventory scores, with higher mean QOL scores being associated with lower mean Beck Depression Inventory scores (P < 0.001). Conclusions: QOL remained stable among PWH who participate in cure-related research at EOL. The inverse relationship between QOL and depressive symptoms suggests that participation in cure-related research may improve QOL or reduce depressive symptoms in this population. Future interventions should look into ways to improve the well-being of PWH at EOL through research and customized mental health interventions.

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.