Targeting Non Viral Markers of HIV Persistence

针对艾滋病毒持续存在的非病毒标志物

• 批准号: 10392921
• 负责人: Timothy Jensen Henrich
• 金额: $ 62.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392921
• 关键词: Antibody-drug conjugates; Aspirate substance; Binding; Bispecific Antibodies; Bispecific Monoclonal Antibodies; Blood; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Cell surface; Cells; Clinical; Clinical Research; Cytometry; DNA; Data; Development; Diagnostic; Disease; Environment; Exposure to; FCGR3B gene; FDA approved; Future; Gene Expression Profile; Genetic Transcription; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; HIV-1; Helper-Inducer T-Lymphocyte; Histone Deacetylase Inhibitor; Immune; Immune Targeting; Immunohistochemistry; In Situ; Individual; Infection; Interleukin-15; Laboratories; Lead; Lymphocyte; Lymphoid Tissue; Malignant Neoplasms; Morbidity - disease rate; Myeloid Cells; Nucleic Acid Hybridization; Participant; Peripheral Blood Mononuclear Cell; Phenotype; Proviruses; RNA; Reporter; Reporting; Research Priority; Residual state; Resolution; Sampling; Source; Surface; T-Cell Activation; T-Lymphocyte; TNFRSF8 gene; Techniques; Technology; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Time; Tissues; Tonsillar Tissue; Tumor Necrosis Factor Receptor; Viral; Viral reservoir; Waxes; antibody-dependent cell cytotoxicity; antiretroviral therapy; antitumor agent; base; clinical development; cohort; exhaustion; genetic regulatory protein; genome sequencing; immune checkpoint; improved; in vitro Model; inhibitor; insight; lymph nodes; member; mortality; multicatalytic endopeptidase complex; next generation sequencing; novel; novel strategies; peripheral blood; purge; targeted treatment; therapeutic target; whole genome

PROJECT SUMMARY/ABSTRACT Despite the ability of combination antiretroviral therapy (ART) to reduce disease-related morbidity and mortality in HIV-1 infection, viral reservoirs persist. Identification of non-viral markers associated with HIV-1 infection that can be used as a therapeutic or diagnostic target is a top research priority. Here, we demonstrate that CD30, a member of the tumor necrosis factor (TNF) receptor superfamily, is preferentially expressed on the surface of HIV-infected peripheral blood CD4+ T cells and that and HIV-1 transcriptional activity is co-localized within blood and gut tissues from participants on suppressive ART. In some individuals, HIV-1 DNA or RNA was exclusively recovered from cells expressing CD30. In further preliminary studies, ex vivo treatment with brentuximab vedotin, an FDA approved monoclonal antibody-drug conjugate (ADC) that targets CD30, resulted in up to a 4 log10 reduction in cell-associated HIV-1 DNA in samples obtained from individuals on ART. Despite these exciting data, several important questions remain. The stability of expression of CD30 and on latently infected blood and tissue-derived cells and the tissue burden and phenotypic relationships between CD30+ cells with other immune cell phenotypes is poorly understood. Even if CD30 expression waxes and wanes in infected cells, continued exposure to CD30 targeted therapies could progressively eliminate much of the reservoir. More potent reductions in HIV burden would be expected in the setting of concomitant anti-C30 therapy and latency reversal. The timing of this proposal is key as there are novel anti-CD30 therapies, such as CD16/CD30 bispecific antibodies to elicit antibody-dependent cellular cytotoxicity, in clinical development. We hypothesize that CD30 expression is stably expressed on HIV-infected, tissue-resident cells and will provide a specific therapeutic or immune target for HIV eradication. These tissue-resident cells can exist in a privileged immune environment and are likely to express markers of T cell activation and immune checkpoint/exhaustion and share features of TFH cells, an important source of persistent HIV. Results from prior cancer studies indicate that expression of key retrovrial regulatory proteins may lead to increased surface CD30 expression. However, latently infected cells may also stably express CD30, as we have observed several ART-suppressed individuals with a large majority of HIV-1 DNA recovered from CD30+ lymphocytes. Our aims are to: (1) determine if CD30 is preferentially and stably expressed on HIV-infected peripheral blood and tissue resident cells in individuals on suppressive ART treated during very early or late infection; (2) determine if ex vivo administration of brentuximab vedotin in conjunction with latency reversal will lead to significant reductions in intact cell-associated HIV DNA in PBMC from ART-suppressed individuals, and (3) determine if CD30 is continuously expressed following development of HIV latency, and define unique transcriptional signatures of HIV infected cells expressing CD30. Determining these signatures will inform on how to maximize CD30 expression on HIV infected cells and to drive future mechanistic studies.

项目总结/文摘