{"title":"A daisy chain of inferences: the role of single-cell and single-genome proviral sequencing in characterizing HIV-1 reservoirs.","authors":"Guinevere Q Lee","doi":"10.1097/COH.0000000000000964","DOIUrl":"https://doi.org/10.1097/COH.0000000000000964","url":null,"abstract":"<p><strong>Purpose of review: </strong>Understanding and targeting the HIV reservoir requires navigating a hierarchy of inferential assays. Quantitative viral outgrowth assays, FLIP-seq, and intact proviral DNA assays (IPDA) - though methodologically distinct - are all fundamentally single-cell technologies. Each relies on limiting dilution to isolate and interrogate individual proviral genomes derived from single infected cells, offering high-resolution proxies for the outcome of greatest interest: replication competence and the risk of viral rebound. Rather than providing direct measurements, these assays infer one another in a nested framework. This review highlights the importance of critically interpreting assay outputs within this chain of inference to guide cure-directed strategies and reservoir quantification.</p><p><strong>Recent findings: </strong>Recent studies emphasize the complexity and limitations of current assays measuring HIV-1 reservoirs. Key themes include reliance on bioinformatics definitions of genome-intactness to infer replication competence, alongside significant limitations due to viral diversity, PCR amplification length biases, and definitional inconsistencies. Modified assays like subtype-specific IPDA aim to address these issues.</p><p><strong>Summary: </strong>Standardized, subtype-specific single-cell methodologies are crucial for accurate HIV reservoir characterization. Future research should integrate large-scale sequencing with replication competence validation, and should refine bioinformatics approaches to enhance predictive accuracy. Enhanced assay precision is essential to inform effective HIV cure strategies.</p>","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michael A Moso, Michael Roche, Paula M Cevaal, Sharon R Lewin
{"title":"CRISPR/Cas9 for achieving postintervention HIV control.","authors":"Michael A Moso, Michael Roche, Paula M Cevaal, Sharon R Lewin","doi":"10.1097/COH.0000000000000963","DOIUrl":"https://doi.org/10.1097/COH.0000000000000963","url":null,"abstract":"<p><strong>Purpose of review: </strong>Recent advances in gene therapy have led to the first clinically approved CRISPR/Cas9 therapy for β-thalassaemia and sickle cell disease. Gene therapy could play an important role in targeting HIV persistence and achieving postintervention HIV control. Here, we review recent updates in CRISPR/Cas9-based HIV gene therapy approaches, including CCR5-editing (protect), proviral targeting (excise or modify), and immune cell engineering (attack).</p><p><strong>Recent findings: </strong>Recent studies provide additional safety data for use of CRISPR/Cas9-based gene therapies, however low in vivo editing efficiency highlights the need for improved delivery methods. This is particularly relevant for strategies requiring transfection of all HIV-infected cells containing intact proviruses, such as proviral excision. For ex vivo editing approaches, poor engraftment and durability of edited cells present additional challenges. Newer methods such as lipid nanoparticle delivery could provide a mechanism to overcome current limitations with ex vivo and in vivo delivery. Several studies have demonstrated proof-of-concept of combination gene therapy approaches, including gene editing strategies to generate HIV-resistant cells with immune effector functions, providing novel approaches to control and durably suppress viral replication.</p><p><strong>Summary: </strong>Several studies have demonstrated feasibility of gene therapy approaches in achieving postintervention HIV control. Improvements in both ex vivo and in vivo delivery methods are required to progress current gene therapy approaches to the clinic.</p>","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Understanding the HIV-specific T-cell response to immune checkpoint blockade: what can we learn from cancer immunotherapy?","authors":"Céline Gubser, Daniel E Kaufmann","doi":"10.1097/COH.0000000000000957","DOIUrl":"https://doi.org/10.1097/COH.0000000000000957","url":null,"abstract":"<p><strong>Purpose of review: </strong>This review examines the potential of immune checkpoint blockade (ICB) to enhance HIV-specific T-cell responses, leveraging insights from cancer immunotherapy to tackle persistent challenges in achieving long-term potent immune response to keep the virus in check. By highlighting lessons from oncology, we aim to discuss innovative strategies to improve HIV treatment outcomes and advance the search for a functional cure.</p><p><strong>Recent findings: </strong>ICB extends beyond targeting PD-1 and CTLA-4, with novel therapies and engineered approaches in cancer also holding promise for HIV treatment. HIV-specific T-cell exhaustion, stemness, T-cell receptor clonal replacement, and antigen load critically influence ICB success, emphasizing the complexity and need for research on innovative strategies that can further enhance treatment efficacy in the context of HIV.</p><p><strong>Summary: </strong>While ICB shows promising potential, its role in HIV cure strategies requires further exploration in clinical trials with people with HIV (PWH). Future research should focus on advancing ICB as a tool for durable HIV control by investigating novel immune checkpoint targets, bispecific antibodies, minimizing toxicity, and identifying biomarkers for effective ICB responses.</p>","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The power of ten in HIV remission: insights from hematopoietic stem cell transplantation.","authors":"Javier Martinez-Picado, Mi Kwon, Maria Salgado","doi":"10.1097/COH.0000000000000954","DOIUrl":"https://doi.org/10.1097/COH.0000000000000954","url":null,"abstract":"<p><strong>Purpose of review: </strong>This review discusses emerging insights from ten cases of HIV remission following allogeneic hematopoietic stem cell transplantation (allo-HSCT). With more than 40 million people living with HIV and current therapies offering lifelong control but not cure, these rare cases of viral remission provide timely and valuable perspectives for designing curative strategies.</p><p><strong>Recent findings: </strong>The review synthesizes clinical experiences from cases such as the Berlin, London, Düsseldorf, City of Hope, and New York patients. These cases have demonstrated that that the achievement of full donor chimerism and the presence of the CCR5Δ32 mutation significantly enhance the likelihood of HIV remission. However, recent evidence, including the Geneva patient, shows that remission may also occur without the mutation, suggesting a pivotal role for alloreactivity in clearing viral reservoirs. Studies also highlight virological, hematological, and immunological markers that are critical for monitoring remission and informing safe interruption of antiretroviral therapy.</p><p><strong>Summary: </strong>Although allo-HSCT is not scalable for all persons living with HIV due to its risks and complexity, the ten cases of remission addressed here have deepened our understanding of HIV persistence and eradication mechanisms. The insights gained may guide the development of more accessible and safer cure strategies in the future.</p>","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Prospects for therapeutic T-cell vaccine strategies for HIV cure.","authors":"Beatriz Mothe, Christian Brander","doi":"10.1097/COH.0000000000000965","DOIUrl":"https://doi.org/10.1097/COH.0000000000000965","url":null,"abstract":"<p><strong>Purpose of review: </strong>This review article aims to summaries the advances in T-cell vaccination as a component of HIV cure strategies. Recent clinical trials of therapeutic vaccination showing small but intriguing efficacy signals, provide the field with the data necessary to embark on informed combination strategies that build on these advances. The review focusses on aspects of T-cell immunogen design and vector use for vaccination, and discusses the effects of adjuvants and combination strategies on vaccine-induced immunity and their impact on virus control in people with HIV who undergo an analytical treatment interruption.</p><p><strong>Recent findings: </strong>Vaccine-induced virus-specific T-cell immunity has been linked to relative control of viral replication in several recent clinical trials. Different immunogen concepts have also entered clinical trials, but for only a few are there immunogenicity and efficacy data available. New initiatives that leverage innate immune mechanisms show some interesting prospect to improve antiviral immunity. The available data also indicate that the preexisting T-cell immunity plays an important role in the strength and breadth of the vaccine-induced immunity.</p><p><strong>Summary: </strong>With some efficacy data supporting the role of antiviral T-cell immunity, strategies that improve this response further can be delineated and incorporated into future, more potent combination approaches.</p>","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Roadmap for spatial transcriptomics of HIV in tissues.","authors":"Qijie Guan, Amare Eshetu, Ya-Chi Ho","doi":"10.1097/COH.0000000000000961","DOIUrl":"10.1097/COH.0000000000000961","url":null,"abstract":"<p><strong>Purpose of review: </strong>Mechanisms of HIV persistence in tissues are distinct from that in the blood. Spatial transcriptomic profiling examines HIV-infected cells, surrounding neighborhoods, and tissue microenvironment in unprecedented resolution. Spatial profiling captures cytokine gradients, distances between HIV-infected cells and immune effectors (and their function versus exhaustion), and cell-cell interactions. We present an overview of spatial transcriptomic platforms and a workflow of quality controls, sanity check, and bioinformatic analysis.</p><p><strong>Recent findings: </strong>The selection of spatial profiling methods should base on the research question, resolution, breadth of coverage, the expression level of RNA of interest, tissue quality, and tissue size. Advanced spatial transcriptomic profiling can capture RNA molecules at high resolution (<1 μm) and thus enable near-single cell profiling at genome-wide (~20 000 genes) breadth. Specifically, poly-A-based mRNA capture can identify previously unknown targets, while targeted RNA capture increases sensitivity in low-quality tissues. In targeted capture, however, the increase in target numbers frequently decreases sensitivity. Coupling ATAC-seq, protein capture, and T cell receptor sequencing to spatial platforms is ongoing.</p><p><strong>Summary: </strong>Spatial transcriptomic profiling uncovers mechanisms of HIV persistence in tissues and informs therapeutic strategies. Investigators should ensure the rigor of analysis, validate findings, and avoid reporting signatures with unknown biological significance.</p>","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144585952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Current insight into HIV-1 persistence from single-cell transcriptome profiling in acutely treated cohorts of infection.","authors":"Lakshmi Rani Iyer, Rasmi Thomas","doi":"10.1097/COH.0000000000000962","DOIUrl":"10.1097/COH.0000000000000962","url":null,"abstract":"<p><strong>Purpose of review: </strong>Antiretroviral therapy is effective in controlling viral load, but there is immediate rebound of virus when treatment is interrupted. This is due to a reservoir of cells harboring HIV which evades immune surveillance and persists in the host. In this review we discuss research leveraging single-cell transcriptomics to examine single-cells from people living with HIV in vivo that can provide insight into these reservoir cells.</p><p><strong>Recent findings: </strong>Advancements in the field of multiomics, specifically single-cell RNA-sequencing (scRNA-seq), have enabled the profiling of hundreds of thousands of single cells and characterized the heterogeneity of cells in people with HIV. Studies in cohorts of people treated during acute HIV-1 infection have revealed longitudinal changes in immune responses during early infection, discovered novel restriction and latency factors, and identified markers of the cells with virus and the reservoir size.</p><p><strong>Summary: </strong>Single-cell transcriptomics is a powerful technology that screens the entire transcriptome of an individual cell. When used strategically to investigate samples from cohorts of acute HIV-1 infection, this unbiased omics tool can shed light on the elusive HIV-1 reservoir and unlock strategies for cure.</p>","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144602626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Carmen M Cano de Luque, Matilde Sánchez-Conde, Fátima Brañas
{"title":"Nonpharmacologic interventions to improve quality of life of older adults with HIV.","authors":"Carmen M Cano de Luque, Matilde Sánchez-Conde, Fátima Brañas","doi":"10.1097/COH.0000000000000937","DOIUrl":"10.1097/COH.0000000000000937","url":null,"abstract":"<p><strong>Purpose of review: </strong>Ensuring optimal quality of life (QOL) in older adults with HIV (OAWH) should be a priority. Comprehensive strategies are needed not only to assess QOL but also to implement targeted interventions that enhance it across multiple dimensions. This review aims to examine the robust scientific evidence supporting the effectiveness of nonpharmacological interventions, such as exercise, socialization, and psychological support.</p><p><strong>Recent findings: </strong>Physical activity and structured exercise programs have been shown to improve functional capacity, reduce frailty, alleviate depressive symptoms, and enhance psychological well being in OAWH. Studies indicate that interventions such as home-based exercise programs, community-based support, and digital health initiatives can help mitigate isolation, reduce depressive symptoms, and improve socialization.</p><p><strong>Summary: </strong>There remains a gap between the scientific evidence demonstrating the benefits of nonpharmacological interventions and their implementation in clinical practice. A shift from disease-centered to person-centered medicine is necessary to adequately address the real needs of OAWH. From a healthcare policy perspective, a fundamental change in approach is essential, with greater investment in evidence-based strategies - such as exercise, socialization, and psychological support - even if it requires rethinking the current care model.</p>","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":"402-408"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Menopause: an opportunity to optimize health and well being for people with HIV.","authors":"Shema Tariq","doi":"10.1097/COH.0000000000000944","DOIUrl":"10.1097/COH.0000000000000944","url":null,"abstract":"<p><strong>Purpose of review: </strong>Menopause, defined as 12 months without menstruation, is a complex biopsychosocial transition. This review synthesizes current knowledge on menopause in individuals living with HIV, highlighting its clinical significance, research gaps, and approaches for optimizing care.</p><p><strong>Recent findings: </strong>Women and people with ovaries with HIV may experience menopause earlier, and with more severe vasomotor, mood, and musculoskeletal symptoms compared to people without HIV. Increasing severity of symptoms is associated with reduced quality of life and poorer engagement in HIV care. Additionally, estrogen depletion combined with HIV increases the risk of cardiometabolic disease and osteoporosis. Biomarkers like AMH have shown promise for assessing ovarian reserve in this population, but current evidence remains inconclusive. Menopause remains under-recognized in HIV care, with low rates of menopausal hormone therapy use and limited provider confidence in menopause management.</p><p><strong>Summary: </strong>Addressing menopause in people with HIV is vital for improving quality of life, supporting engagement in HIV care, and reducing comorbidity risk. Integrated and holistic care models, peer support, and focused research are essential to meet the needs of this growing population and close existing gaps in care.</p>","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":"388-395"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144045709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Balancing polypharmacy and comorbidity management: cardiovascular health.","authors":"Alex E Rock, Matthew L Russell, Virginia A Triant","doi":"10.1097/COH.0000000000000948","DOIUrl":"10.1097/COH.0000000000000948","url":null,"abstract":"<p><strong>Purpose of review: </strong>This review will discuss statin therapy for prevention of cardiovascular disease (CVD) among people with HIV (PWH) in the context of balancing prevention and treatment of chronic diseases with challenges related to polypharmacy.</p><p><strong>Recent findings: </strong>Aging PWH confront an increased risk of chronic diseases, resulting in the need for prevention and treatment of comorbidities in addition to antiretroviral therapy (ART). Paradigm-shifting data from the REPRIEVE trial demonstrated a reduction in CVD events with statin therapy among PWH at low to moderate CVD risk, prompting the Department of Health and Human Services (HHS) to recommend statin therapy for primary prevention of CVD in people with HIV aged 40-75 years. Statins should be initiated according to guideline recommendations for CVD prevention, and discussion of statin initiation should include consideration of concurrent medications and the potential effects of polypharmacy.</p><p><strong>Summary: </strong>Statins should be initiated for primary prevention of CVD in people with HIV age 40-75 years. The effects of polypharmacy should be considered in all aging PWH. Prevention and treatment of chronic diseases among PWH is important to reduce morbidity and mortality and promote healthy aging.</p>","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":"409-415"},"PeriodicalIF":0.0,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}