Current opinion in HIV and AIDS最新文献_第9页

What's in a cure: designing a broad-spectrum HIV gene therapy. 治疗的意义：设计一种广谱的艾滋病基因疗法。

Current opinion in HIV and AIDS Pub Date : 2024-05-01 Epub Date: 2024-03-01 DOI: 10.1097/COH.0000000000000846

Rachel E Berman, Will Dampier, Michael R Nonnemacher, Brian Wigdahl

{"title":"What's in a cure: designing a broad-spectrum HIV gene therapy.","authors":"Rachel E Berman, Will Dampier, Michael R Nonnemacher, Brian Wigdahl","doi":"10.1097/COH.0000000000000846","DOIUrl":"10.1097/COH.0000000000000846","url":null,"abstract":"Purpose of review: The leading gene editing strategy for a human immunodeficiency virus type 1 (HIV-1) cure involves the delivery of SaCas9 and two guide RNAs (gRNAs) in an adeno-associated viral (AAV) vector. As a dual-component system, CRISPR is targeted to a genetic locus through the choice of a Cas effector and gRNA protospacer design pair. As CRISPR research has expanded in recent years, these components have been investigated for utilization in cure strategies, which will be discussed in this article.Recent findings: Type II SpCas9 and SaCas9 have been the leading Cas effectors across gene editing therapeutics to date. Additionally, extensive research has expanded the potential to multiplex gRNAs and target them effectively to the highly genetically diverse HIV-1 provirus. More recently, the Type V family of Cas12 effectors opens a new opportunity to use a smaller Cas protein for packaging into an AAV vector with multiplexed gRNAs.Summary: In understanding the individual components of a CRISPR/Cas therapeutic cure for HIV-1, it is important to know that the currently used strategies can be improved upon. Future areas will include alternative smaller Cas effectors, multiplexed gRNAs designs, and/or alternative delivery modalities.","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":"150-156"},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11188629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140320184","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}

引用次数: 0

Pediatric immunotherapy and HIV control 儿童免疫疗法和艾滋病毒控制

Current opinion in HIV and AIDS Pub Date : 2024-05-01 DOI: 10.1097/coh.0000000000000857

T. T. Chinunga, A. Chahroudi, Susan P. Ribeiro

{"title":"Pediatric immunotherapy and HIV control","authors":"T. T. Chinunga, A. Chahroudi, Susan P. Ribeiro","doi":"10.1097/coh.0000000000000857","DOIUrl":"https://doi.org/10.1097/coh.0000000000000857","url":null,"abstract":"\u0000 \u0000 Highlighting opportunities/potential for immunotherapy by understanding dynamics of HIV control during pediatric HIV infection with and without antiretroviral therapy (ART), as modeled in Simian immunodeficiency virus (SIV) and Simian-human immunodeficiency virus (SHIV)-infected rhesus macaques and observed in clinical trials. This review outlines mode of transmission, pathogenesis of pediatric HIV, unique aspects of the infant immune system, infant macaque models and immunotherapies.\u0000 \u0000 \u0000 \u0000 During the earliest stages of perinatal HIV infection, the infant immune system is characterized by a unique environment defined by immune tolerance and lack of HIV-specific T cell responses which contribute to disease progression. Moreover, primary lymphoid organs such as the thymus appear to play a distinct role in HIV pathogenesis in children living with HIV (CLWH). Key components of the immune system determine the degree of viral control, targets for strategies to induce viral control, and the response to immunotherapy. The pursuit of highly potent broadly neutralizing antibodies (bNAbs) and T cell vaccines has revolutionized the approach to HIV cure. Administration of HIV-1-specific bNAbs, targeting the highly variable envelope improves humoral immunity, and T cell vaccines induce or improve T cell responses such as the cytotoxic effects of HIV-1-specific CD8+ T cells, both of which are promising options towards virologic control and ART-free remission as evidenced by completed and ongoing clinical trials.\u0000 \u0000 \u0000 \u0000 Understanding early events during HIV infection and disease progression in CLWH serves as a foundation for predicting or targeting later outcomes by harnessing the immune system's natural responses. The developing pediatric immune system offers multiple opportunities for specific long-term immunotherapies capable of improving quality of life during adolescence and adulthood.\u0000","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":"50 153","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141044357","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}

引用次数: 0

"Block and lock" viral integration sites in persons with drug-free control of HIV-1 infection. 无药物控制 HIV-1 感染者的 "阻断和锁定 "病毒整合位点。

Current opinion in HIV and AIDS Pub Date : 2024-05-01 Epub Date: 2024-02-28 DOI: 10.1097/COH.0000000000000845

Benjamin Bone, Mathias Lichterfeld

{"title":"\"Block and lock\" viral integration sites in persons with drug-free control of HIV-1 infection.","authors":"Benjamin Bone, Mathias Lichterfeld","doi":"10.1097/COH.0000000000000845","DOIUrl":"10.1097/COH.0000000000000845","url":null,"abstract":"Purpose of review: Elite controllers (ECs) and Posttreatment controllers (PTCs) represent a small subset of individuals who are capable of maintaining drug-free control of HIV plasma viral loads despite the persistence of a replication-competent viral reservoir. This review aims to curate recent experimental studies evaluating viral reservoirs that distinguish EC/PTC and may contribute to their ability to maintain undetectable viral loads in the absence of antiretroviral therapy.Recent findings: Recent studies on ECs have demonstrated that integration sites of intact proviruses in EC/PTC are markedly biased towards heterochromatin regions; in contrast, intact proviruses in accessible and permissive chromatin were profoundly underrepresented. Of note, no such biases were noted when CD4 + T cells from EC were infected directly ex vivo, suggesting that the viral reservoir profile in EC is not related to altered integration site preferences during acute infection, but instead represents the result of immune-mediated selection mechanisms that can eliminate proviruses in transcriptionally-active euchromatin regions while promoting preferential persistence of intact proviruses in nonpermissive genome regions. Proviral transcription in such \"blocked and locked\" regions may be restricted through epigenetic mechanisms, protecting them from immune-recognition but presumably limiting their ability to drive viral rebound. While the exact immune mechanisms driving this selection process remain undefined, recent single-cell analytic approaches support the hypothesis that HIV reservoir cells are subject to immune selection pressure by host factors.Summary: A \"blocked and locked\" viral reservoir profile may constitute a structural virological correlate of a functional cure of HIV-1 infection. Further research into the immunological mechanism promoting HIV-1 reservoir selection and evolution in EC/PTC is warranted and could inform foreseeable cure strategies.","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":"110-115"},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140061570","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}

引用次数: 0

New latency-promoting agents for a block-and-lock functional cure strategy. 用于阻断和锁定功能性治疗策略的新型延迟促进剂。

Current opinion in HIV and AIDS Pub Date : 2024-05-01 Epub Date: 2024-02-27 DOI: 10.1097/COH.0000000000000844

Eline Pellaers, Alexe Denis, Zeger Debyser

{"title":"New latency-promoting agents for a block-and-lock functional cure strategy.","authors":"Eline Pellaers, Alexe Denis, Zeger Debyser","doi":"10.1097/COH.0000000000000844","DOIUrl":"10.1097/COH.0000000000000844","url":null,"abstract":"Purpose of review: Currently, HIV-infected patients are treated with antiretroviral therapy. However, when the treatment is interrupted, viral rebound occurs from latently infected cells. Therefore, scientists aim to develop an HIV-1 cure which eradicates or permanently silences the latent reservoir.Recent findings: Previously, scientists focused on the shock-and-kill cure strategy, which aims to eradicate the latent reservoir using latency-reactivating agents. Limited success shifts the interest towards the block-and-lock cure approach, which aims to achieve a functional cure by \"blocking\" HIV-1 transcription and \"locking\" the provirus in a deep latent state, resistant to treatment-interruption. In this strategy, latency promoting agents are used to induce transcriptional silencing and alter the epigenetics environment at the HIV promotor.Summary: For the block-and-lock cure strategy to succeed more investigation into the transcriptional and epigenetic regulation of HIV-1 gene expression is necessary to design optimal latency-promoting agents. In this review, we will discuss the latency promoting agents that have been described in literature during the past 2 years (2022-2023).","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":"95-101"},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10990034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140061572","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}

引用次数: 0

Persistent HIV-1 transcription during ART: time to reassess its significance? 抗逆转录病毒疗法期间持续存在的 HIV-1 转录：是时候重新评估其意义了吗？

Current opinion in HIV and AIDS Pub Date : 2024-05-01 Epub Date: 2024-03-12 DOI: 10.1097/COH.0000000000000849

Céline Fombellida-Lopez, Ben Berkhout, Gilles Darcis, Alexander O Pasternak

{"title":"Persistent HIV-1 transcription during ART: time to reassess its significance?","authors":"Céline Fombellida-Lopez, Ben Berkhout, Gilles Darcis, Alexander O Pasternak","doi":"10.1097/COH.0000000000000849","DOIUrl":"10.1097/COH.0000000000000849","url":null,"abstract":"Purpose of review: Despite suppressive antiretroviral therapy (ART), HIV-1 reservoirs persist and reignite viral replication if therapy is interrupted. Persistence of the viral reservoir in people with HIV-1 (PWH) is the main obstacle to an HIV-1 cure. The reservoirs are not transcriptionally silent, and viral transcripts can be detected in most ART-treated individuals. Here, we review the recent progress in the characterization of persistent HIV-1 transcription during ART.Recent findings: Evidence from several studies indicates that, although cell-associated unspliced (US) HIV-1 RNA is abundantly expressed in ART-treated PWH, intact full-length US transcripts are rare and most US RNA is derived from defective proviruses. The transcription- and translation-competent defective proviruses, previously considered irrelevant, are increasingly being linked to residual HIV-1 pathogenesis under suppressive ART. Recent data suggest a continuous crosstalk between the residual HIV-1 activity under ART and the immune system. Persistent HIV-1 transcription on ART, despite being mostly derived from defective proviruses, predicts viral rebound upon therapy interruption, suggesting its role as an indicator of the strength of the host antiviral immune response that is shaping the viral rebound.Summary: In light of the recent findings, the significance of persistent HIV-1 transcription during ART for the long-term health of PWH and the cure research should be reassessed.","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":"124-132"},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10990031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140178334","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}

引用次数: 0

Editorial introduction. 编辑介绍。

Current opinion in HIV and AIDS Pub Date : 2024-05-01 Epub Date: 2024-04-04 DOI: 10.1097/COH.0000000000000852

引用次数: 0

Harnessing natural killer cells to target HIV-1 persistence. 利用自然杀伤细胞遏制 HIV-1 的持续存在。

Current opinion in HIV and AIDS Pub Date : 2024-05-01 Epub Date: 2024-02-28 DOI: 10.1097/COH.0000000000000848

Vinita R Joshi, Marcus Altfeld

{"title":"Harnessing natural killer cells to target HIV-1 persistence.","authors":"Vinita R Joshi, Marcus Altfeld","doi":"10.1097/COH.0000000000000848","DOIUrl":"10.1097/COH.0000000000000848","url":null,"abstract":"Purpose of review: The purpose of this article is to review recent advances in the role of natural killer (NK) cells in approaches aimed at reducing the latent HIV-1 reservoir.Recent findings: Multiple approaches to eliminate cells harboring latent HIV-1 are being explored, but have been met with limited success so far. Recent studies have highlighted the role of NK cells and their potential in HIV-1 cure efforts. Anti-HIV-1 NK cell function can be optimized by enhancing NK cell activation, antibody dependent cellular cytotoxicity, reversing inhibition of NK cells as well as by employing immunotherapeutic complexes to enable HIV-1 specificity of NK cells. While NK cells alone do not eliminate the HIV-1 reservoir, boosting NK cell function might complement other strategies involving T cell and B cell immunity towards an HIV-1 functional cure.Summary: Numerous studies focusing on targeting latently HIV-1-infected cells have emphasized a potential role of NK cells in these strategies. Our review highlights recent advances in harnessing NK cells in conjunction with latency reversal agents and other immunomodulatory therapeutics to target HIV-1 persistence.","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":"141-149"},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140061571","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}

引用次数: 0

The sounds of silencing: dynamic epigenetic control of HIV latency. 沉默的声音：艾滋病毒潜伏期的动态表观遗传控制。

Current opinion in HIV and AIDS Pub Date : 2024-05-01 Epub Date: 2024-03-12 DOI: 10.1097/COH.0000000000000850

Kien Nguyen, Jonathan Karn

{"title":"The sounds of silencing: dynamic epigenetic control of HIV latency.","authors":"Kien Nguyen, Jonathan Karn","doi":"10.1097/COH.0000000000000850","DOIUrl":"10.1097/COH.0000000000000850","url":null,"abstract":"Purpose of review: This review highlights advances in understanding the epigenetic control mechanisms that regulate HIV-1 latency mechanisms in T-cells and microglial cells and describes the potential of current therapeutic approaches targeting the epigenetic machinery to eliminate or block the HIV-1 latent reservoir.Recent findings: Large-scale unbiased CRISPR-Cas9 library-based screenings, coupled with biochemical studies, have comprehensively identified the epigenetic factors pivotal in regulating HIV-1 latency, paving the way for potential novel targets in therapeutic development. These studies also highlight how the bivalency observed at the HIV-1 5'LTR primes latent proviruses for rapid reactivation.Summary: The HIV-1 latent is established very early during infection, and its persistence is the major obstacle to achieving an HIV-1 cure. Here, we present a succinct summary of the latest research findings, shedding light on the pivotal roles played by host epigenetic machinery in the control of HIV-1 latency. Newly uncovered mechanisms permitting rapid reversal of epigenetic restrictions upon viral reactivation highlight the formidable challenges of achieving enduring and irreversible epigenetic silencing of HIV-1.","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":"102-109"},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10990033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140320183","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}

引用次数: 0

Strategies to target the central nervous system HIV reservoir. 针对中枢神经系统艾滋病病毒库的策略。

Current opinion in HIV and AIDS Pub Date : 2024-05-01 Epub Date: 2024-02-29 DOI: 10.1097/COH.0000000000000847

Andrea Mastrangelo, Lucio Gama, Paola Cinque

{"title":"Strategies to target the central nervous system HIV reservoir.","authors":"Andrea Mastrangelo, Lucio Gama, Paola Cinque","doi":"10.1097/COH.0000000000000847","DOIUrl":"10.1097/COH.0000000000000847","url":null,"abstract":"Purpose of the review: The central nervous system (CNS) is an hotspot for HIV persistence and may be a major obstacle to overcome for curative strategies. The peculiar anatomical, tissular and cellular characteristics of the HIV reservoir in the CNS may need to be specifically addressed to achieve a long-term HIV control without ART. In this review, we will discuss the critical challenges that currently explored curative strategies may face in crossing the blood-brain barrier (BBB), targeting latent HIV in brain-resident myeloid reservoirs, and eliminating the virus without eliciting dangerous neurological adverse events.Recent findings: Latency reversing agents (LRA), broadly neutralizing monoclonal antibodies (bNabs), chimeric antigen receptor (CAR) T-cells, and adeno-associated virus 9-vectored gene-therapies cross the BBB with varying efficiency. Although brain penetration is poor for bNAbs, viral vectors for in vivo gene-editing, certain LRAs, and CAR T-cells may reach the cerebral compartment more efficiently. All these approaches, however, may encounter difficulties in eliminating HIV-infected perivascular macrophages and microglia. Safety, including local neurological adverse effects, may also be a concern, especially if high doses are required to achieve optimal brain penetration and efficient brain cell targeting.Summary: Targeting the CNS remains a potential problem for the currently investigated HIV curing strategies. In vivo evidence on CNS effectiveness is limited for most of the investigated strategies, and additional studies should be focused on evaluating the interplay between the cerebral HIV reservoir and treatment aiming to achieve an ART-free cure.","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":"133-140"},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140061573","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}

引用次数: 0

The multifaceted nature of HIV tissue reservoirs. 艾滋病毒组织库的多面性。

Current opinion in HIV and AIDS Pub Date : 2024-05-01 Epub Date: 2024-03-11 DOI: 10.1097/COH.0000000000000851

Riddhima Banga, Matthieu Perreau

{"title":"The multifaceted nature of HIV tissue reservoirs.","authors":"Riddhima Banga, Matthieu Perreau","doi":"10.1097/COH.0000000000000851","DOIUrl":"10.1097/COH.0000000000000851","url":null,"abstract":"Purpose of review: To underline the complexity and the heterogeneity of the HIV reservoir.Recent findings: While lymphoid tissues (spleen, lymph nodes, gut-associated lymphoid tissue) harbor specific subsets of specialized CD4 + T cells enriched in HIV-infected cells, non-CD4 + T cell reservoirs such as tissue-resident macrophages and dendritic cells have also been implicated to contribute to viral persistence. Moreover, studies have applied highly sensitive tools to detect transcriptional activity within HIV-infected cells during prolonged ART and revealed a broader spectrum of transcriptional activity for proviruses than previously thought. Finally, while a combination of factors might be involved in the regulation of HIV persistence within different tissues and remains to be fully elucidated, recent results from autopsy samples of HIV-infected ART suppressed individuals indicate extensive clonality of HIV reservoirs in multiple tissues and suggest that the recirculation of HIV-infected cells and their local expansions in tissues may also contribute to the complexity of the HIV reservoirs in humans.Summary: HIV persistence in blood and multiple tissues despite long-standing and potent therapy is one of the major barriers to a cure. Given that the HIV reservoir is established early and is highly complex based on its composition, viral diversity, tissue distribution, transcriptional activity, replication competence, migration dynamics and proliferative potential across the human body and possible compartmentalization in specific tissues, combinatorial therapeutic approaches are needed that may synergize to target multiple viral reservoirs to achieve a cure for HIV infection.","PeriodicalId":93966,"journal":{"name":"Current opinion in HIV and AIDS","volume":" ","pages":"116-123"},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10990014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140320182","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}

引用次数: 0