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Loss of Y-chromosome as a driver of HIV-1 latency

Y 染色体丢失是 HIV-1 潜伏期的驱动因素

基本信息

批准号：
10882257
负责人：
OLAF KUTSCH
金额：
$ 42.43万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-16 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10882257
关键词：
Address Aging Binding Sites CD28 gene CD3 Antigens CD4 Positive T Lymphocytes Cell Line Cells Chromatin Chromosome abnormality Complex Data Development Drug Targeting Environment Event Exhibits Female Genes HIV HIV Infections HIV resistance HIV-1 Heterogeneity Histones IL8 gene Immunologics Impairment In Vitro Individual Infection Interleukin Gene Interleukin-2 Laboratories Long Terminal Repeats Mediating Memory Modeling Modification Monoclonal Antibodies Numerical Chromosomal Abnormality Patients Persons Phase Phenotype Play Population Positioning Attribute Premature aging syndrome Proteomics Proviruses RNA Polymerase II Reporting Resistance Rest Role Series Sex Chromosomes Signal Transduction Splenocyte Stress Surrogate Markers T-Lymphocyte Therapeutic Intervention Viral Viral reservoir Virus Latency Y Chromosome age effect antiretroviral therapy chromosome X loss chromosome Y loss curative treatments early onset exhaustion in vitro Model insight integration site latent HIV reservoir latent infection male member novel therapeutic intervention phenotypic biomarker phosphoproteomics promoter proteomic signature response response biomarker single cell analysis single-cell RNA sequencing targeted treatment therapeutic development therapeutic evaluation transcription factor transcriptomics

项目摘要

ABSTRACT The presence of extensive heterogeneity between individual latently HIV-1 infected T cells suggests that latent HIV-1 infection can persist under greatly differing host cell conditions. While we and others have described the biomolecular phenotype of latently infected T cells, the biomolecular driver(s) of these stable phenotypic changes remain unknown. For primary T cells, the transition to a resting memory state or T cell exhaustion effects may play a role, but latent infection is also found in naïve T cells or TfH cells suggesting additional contributing mechanisms. Leading to this application, we addressed the question whether HIV infection can trigger an irreversible modification of host cells that can explain the stability of latent infection events, and could occur independent of memory status or CD4+ T cell subtype. We show that latently infected T cell lines and a large percentage of in vitro generated latently infected primary T cells, when derived from male donors, exhibited a Loss of Y-chromosome (LOY) phenotype. Numerical chromosomal aberrations, including the loss of sex chromosomes, cause nonlinear transcriptomic changes, which would explain the observed extensive transcriptomic heterogeneity between individual latently HIV-1 infected T cells. Extensive transcriptomic changes can also result in impaired cellular signaling, and explain the widely differing reactivation response spectrum between individual cells. For primary T cells, we demonstrate that latent HIV-1 infection events in LOY cells are largely resistant to TCR/CD3-complex activation mediated reactivation, while latently infected T cells in possession of their Y-chromosome promoted HIV-1 reactivation following TCR/CD3 activation. Loss of Y- chromosome phenomena could thus explain the presence of a reactivation-resistant reservoir that has been first described by the Siliciano group. As LOY is irreversible, this is the first report of a biomolecular alteration that can mechanistically explain HIV-1 latency stability and reactivation inertness, which we consider the major hurdle to viral eradication. In this application we will extend our studies on the correlation of LOY and reactivation resistant HIV-1 latency. Our discovery provides us with the unique opportunity to separate the two phenotypic parts of the latent reservoir based on a causative mechanism (LOY) that has functional consequences (reactivation resistance), which will allow for the exploration and development of therapeutic strategies to individually target these reservoir components using single cell analysis approaches (Aim 1). In parallel we will investigate whether similar latency phenotypes can be found in T cells from female donors and whether loss of X-chromosome (LOX), the most frequent numerical chromosomal aberration in females, plays a similar role for HIV-1 latency control than LOY (Aim 2). The insights generated from this proposal should provide fundamental new insights into HIV-1 latency control and guide the development of new therapeutic strategies to target the latent HIV-1 reservoir, specifically the reactivation-resistant part of the HIV-1 reservoir.

摘要