Current opinion in HIV and AIDS最新文献

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Purpose of review: This review outlines current model systems of HIV latency and their analysis with single-cell omics technologies. Previous studies have used bulk analyses of infected cell cultures to determine mechanisms of HIV transcription and to identify targets associated with HIV latency in vitro . However, heterogeneity in cell populations creates a barrier to the effectiveness of latency reversing agents. Single cell approaches promise to accelerate our understanding of how the host cell environment regulates complex behaviors of the HIV provirus.

Recent findings: Several recent papers have applied cutting edge single cell omics methods to model systems of HIV latency, including scRNAseq and scATACseq, as well as multiomic methods such as DOGMAseq and ECCITEseq. These papers have revealed complex heterogeneity in latently infected cells but have also led to the identification of several new host cell genes that regulate HIV latency.

Summary: Single-cell technologies provide sensitive detection of cellular subpopulations that contribute to proviral reactivation and latency, making them advantageous to apply to widely used cell line and primary cell models of HIV latency. These studies have increased our understanding of HIV latency model systems and generated novel hypotheses which can be tested in clinical samples from people with HIV.

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Purpose of review: This review summarizes recent insights into Fc-mediated immunological mechanisms in viral infections with particular focus in HIV-1 infection. It highlights the versatility of Fc-mediated antibody functions, specially through interactions with Fc receptors (FcRs). The aim is to highlight the importance of Fc-specific properties and their role in mediating distinct effector and immunomodulatory functions.

Recent findings: Recent studies highlight the importance of specific IgG isotypes, Fc-point mutations, Fc-glycosylation and FcR-expressing NK cell subsets in driving efficient Fc-mediated control of viral infections. They show the superiority of IgG3 and afucosylated antibodies in mediating efficient effector functions such as complement- and antibody-dependent cellular cytotoxicity (CDC, ADCC) as well as antibody-dependent cellular phagocytosis (ADCP) in a cell-dependent manner. Furthermore, these studies identify novel Fc mutants with selective FcR binding, enabling more precise harnessing of effector functions.

Summary: Multiple Fc-mediated immune functions of antibodies are crucial for controlling viral spread and eliciting host immune responses. A deeper understanding of antibody interactions with immune actors is key for developing innovative vaccine designs and enhanced antibody-based immunotherapies. The challenge now is to leverage the diverse Fc-mediated antiviral mechanisms to develop optimized therapeutic strategies that not only hinder viral spread but also strengthen protective immunity.

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Purpose of review: 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).

Recent findings: 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.

Summary: 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.

Purpose of review: This review highlights recent advances in single cell "-omics" technologies that have transformed our understanding of the HIV reservoir in the central nervous system (CNS) and cerebrospinal fluid (CSF).

Recent findings: Recent studies have applied single cell and single nucleus RNA-seq, ATAC-seq, CITE-seq, AIRR-seq, multiomic platforms, and spatial transcriptomics to postmortem brain tissues and CSF. These analyses have revealed that HIV persists in rare subsets of CNS-resident microglia and trafficking CD4 + T cells despite ART. Infected microglia often display inflammatory transcriptional states, while clonal T cell populations harboring HIV can migrate between blood and CSF. Spatial and multimodal approaches are uncovering both the tissue localization and epigenetic regulation of infected cells, offering unprecedented insight into reservoir biology and neuropathogenesis.

Summary: Single cell studies have established the CNS as a transcriptionally active and clonally maintained reservoir of HIV during ART. These findings underscore the need for cure strategies that penetrate the brain, target both lymphoid and myeloid reservoirs, and consider the transcriptional, epigenetic and spatial context of HIV-infected cells. Ongoing technological advances will further illuminate the dynamics of the CNS reservoir and guide the design of diagnostic, prognostic and therapeutic biomarkers and CNS-penetrant therapeutic interventions.