Specific killing of latently HIV-1-infected cells after provirus reactivation

原病毒重新激活后特异性杀死潜伏 HIV-1 感染的细胞

• 批准号: 9276563
• 负责人: Qigui Q Yu
• 金额: $ 38.64万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276563
• 关键词: Anti-Retroviral Agents; Antibodies; Antibody Response; Autologous; Biological Assay; CD4 Positive T Lymphocytes; Cell Line; Cells; Chronic; Complement; Complement Activation; Cytolysis; Detection; Diagnostic; Failure; Gene Expression; Goals; Grant; HIV-1; Highly Active Antiretroviral Therapy; Human; Immune response; Immunity; Impairment; In Vitro; Individual; Infection; Interleukin-7; Measurable; Mediating; Medical; Memory; Modeling; Morbidity - disease rate; Patients; Pharmaceutical Preparations; Phase; Production; Proliferating; Proviruses; Public Health; Reporting; Research; Residual state; Rest; Surface; T-Lymphocyte; Testing; Vaccines; Valproic Acid; Viral; Viral Cytopathogenic Effect; Viral Proteins; Viremia; Virion; Virus; Vorinostat; antiretroviral therapy; cell type; effective therapy; experience; global health; improved; in vivo; inhibitor/antagonist; innovation; killings; member; mortality; novel strategies; pandemic disease; prostratin; purge

PROJECT SUMMARY/ABSTRACT The HIV-1 pandemic has claimed over 20 million lives, with 38.6 million people worldwide currently infected, and will continue to be a significant global health problem as there is no vaccine available. Currently, the only effective treatment available to HIV-1 infection is HAART (highly active antiretroviral therapy), which has led to a profound reduction in HIV-1-related morbidity and mortality. However, HAART fails to eliminate the virus in vivo, mainly due to the persistent existence of long-lived latently-infected cells harboring replication-competent proviruses. Efforts to purge these infected cells have focused on reactivation of the proviruses. It is presumed that these infected cells will be killed after reactivation of virus gene expression by viral cytopathic effects (CPEs), host immune responses or both. Several stimulants including IL-7, valproic acid (VPA), suberoylanilide hydroxamic acid (SAHA) and prostratin have been explored to force activation of proviruses in latently-infected resting CD4+ T cells that constitute the major reservoir of HIV-1 in vivo. However, treatment with IL-7 or VPA in patients on HAART has failed to reduce HIV-1 latency, suggesting that these agents alone are not sufficient to induce killing of latently-infected cells. We propose to develop an “activation-killing” approach by combining provirus stimulants with an agent that is able to allow anti-HIV-1 immunity naturally mounted in patients during HIV-1 infection to specifically kill latently-infected cells after provirus reactivation. Studies have shown that both HIV-1-infected cells and virions use their surface regulators of complement activation (RCA) to resist antibody- dependent complement-mediated lysis (ADCML), which explains why vigorous and sustained anti-HIV-1 envelope (Env) antibody (Ab) responses in almost all infected individuals fail to control HIV-1 infection. We and others have reported that blocking human CD59 (hCD59), a key member of RCA, renders both HIV-1-infected cells and virions sensitive to ADCML. We therefore hypothesize that addition of an hCD59 inhibitor to SAHA, prostratin or both will enable anti-HIV-1 Env Abs naturally present in HIV-1-infected individuals to trigger ADCML of latently-infected T cells after provirus reactivation. The provirus stimulants will activate proviruses to express viral proteins on the surface of latently-infected cells that will be killed by ADCML if hCD59 is inhibited. We will use the human T cell line ACH2, a well-characterized model of HIV-1-latency, to develop such an approach (Aim 1, R21 Phase). We will verify whether the approach is able to trigger ADCML of the primary CD4+ T cells latently infected with HIV-1 in vitro (Aim 2, R33 Phase). We will then determine if this approach can allow anti-HIV-1 Abs naturally present in the sera of infected patients to trigger autologous ADCML of their own latently-infected resting CD4+ T cells (Aim 3, R33 Phase). Our project is innovative and significant because we aim to develop a novel approach for purging the persistent reservoir of HIV-1 in patients on HAART. This approach may simultaneously target various latently infected cells and residual viremia, potentially leading to a broader impact and improved efficacy against the various persistent HIV-1 reservoirs.

项目总结/文摘