Phenotypic analysis of latently infected CD4+ T cells.

潜伏感染的 CD4 T 细胞的表型分析。

• 批准号: 8610757
• 负责人: JOEL N BLANKSON
• 金额: $ 22.84万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-05 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610757
• 关键词: Antibodies; BCL2 gene; Binding; CD4 Positive T Lymphocytes; Cell Surface Proteins; Cell surface; Cells; DNA; Development; Dose; Frequencies; Gene Expression; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; In Vitro; Individual; Infection; Lead; Libraries; Life; Mitogens; Modeling; Monoclonal Antibodies; Patients; Phase; Phenotype; Physiology; Population; Regimen; Rest; Sorting - Cell Movement; Surface; System; T-Lymphocyte; Toxin; Tumor Debulking; Viral Genes; Virus; Vorinostat; Work; antibody conjugate; antiretroviral therapy; cellular transduction; chemotherapy; gag Gene Products; in vivo; memory CD4 T lymphocyte; novel; optimism; physiologic model; public health relevance; screening; small molecule; tumor

DESCRIPTION: There has been a lot of optimism about potentially eradicating HIV-1 using strategies such as reactivation of latently infected cells by small molecules. A recent study has suggested that this approach may in fact be possible; a single dose of the molecule vorinostat was shown to induce HIV expression in CD4+ T cells in vivo. While this strategy may end up being effective, it may be very challenging to reactivate every last latently infected CD4+ T cell. A complementary strategy may be to physically eliminate latently infected cells using antibodies conjugated to toxins. This may be analogous to surgically "debulking" a tumor prior to initiating chemotherapy. However, targeting latently infected CD4+ T cells has been a challenging task because the phenotype of these cells remains largely unknown. In this new proposal, we plan to use antibodies to more than 200 different T cell markers in order to determine the phenotype of latently infected CD4+ T cells. Such an approach has been successfully used to determine the phenotype of activated T cells in a recent study. This will be analogous to screening for small molecules that activate latently infected CD4+ T cells, but in this case, a library of monoclonal antibodies (Mabs) rather than compounds will be used and the readout will be binding of Mabs to infected resting CD4+ T cells or recently reactivated latently infected CD4+ T cells rather than reactivation itself. We plan to validate our results by sorting resting CD4+ T cells from HIV-1 infected patients on suppressive HAART regimens. We specifically will sort for markers that are identified in our screen to determine whether there is an overrepresentation of HIV-1 DNA and latent replication-competent virus in these cells. This work will have major implications for strategies for HIV-1 eradication since it will potentially lead to the clearance of latently infectd cells.

描述：人们对利用小分子重新激活潜伏感染细胞等策略来根除HIV-1抱有很大的乐观态度。最近的一项研究表明，这种方法实际上是可能的；单剂量的分子伏立诺他可在体内诱导CD4+ T细胞中的HIV表达。虽然这种策略最终可能是有效的，但重新激活每一个潜伏感染的CD4+ T细胞可能非常具有挑战性。