ANTIBODY NEUTRALIZATION AND ESCAPE IN SUBTYPE C HIV-1

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 HIV-1感染中的中和抗体针对包膜（Env）糖蛋白gp 120和gp 41。然而，HIV-1 Env利用高度有效但定义不明确的机制来逃避抗体介导的中和。这些研究的目的是确定最初的B细胞靶点，并确定分别在卢旺达和赞比亚新感染A亚型和C亚型HIV-1的受试者中病毒逃逸的机制。 在该R 01的第03年，通过与Guido Silvestri博士的合作，我们比较了HIV-1感染与SIV感染天然宿主种属白眉猴中自体病毒的中和抗体（Nab）反应（Li et al）。我们证明了高滴度Nab在HIV-1感染早期发展，并持续到感染的慢性阶段。然而，SIV感染的mangabeys不引起针对自体病毒的高滴度Nab应答。这一发现表明致病性与非致病性感染中B细胞反应的根本差异，我们将继续研究这一观察结果背后的生物学。我们已经证明，与健康人受试者相比，慢性HIV-1感染中的B细胞表达增加的PD-1水平和降低的BTLA水平（Boliar等）。这些标志物的表达与整个B细胞亚群的免疫激活增加和免疫球蛋白的异常产生有关。我们正在继续研究这些异常是如何导致疾病进展和HIV-1感染中体液免疫应答失败的。 资金来源： NIH

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Neutralizing antibodies in HIV-1 infection are directed against the envelope (Env) glycoproteins gp120 and gp41. However, HIV-1 Env utilizes highly effective, but poorly defined, mechanisms to evade antibody-mediated neutralization. The objective of these studies is to indentify the initial B cell targets and define mechanisms of viral escape in subjects that are newly infected with subtype A and C HIV-1 in Rwanda and Zambia, respectively. In year 03 of this R01, through collaboration with Dr. Guido Silvestri, we compared neutralizing antibody (Nab) responses against the autologous virus in HIV-1 infection vs. SIV infection of a natural host species, the sooty mangabey (Li et al). We demonstrated that high titer Nab develops in early HIV-1 infection and persists into the chronic stage of infection. However, SIV infection of sooty mangabeys does not elicit high titer Nab responses against the autologous virus. This finding suggests fundamental differences in the B cell response in pathogenic vs. nonpathogenic infection, and we are continuing to investigate the biology underlying this observation. We have demonstrated that B cells in chronic HIV-1 infection express increased levels of PD-1 and decreased levels of BTLA, compared to healthy human subjects (Boliar et al.). Expression of these markers was linked to increased immune activation throughout the B cells subsets and to the aberrant production of immunoglobulin. We are continuing to investigate how these abnormalities contribute to disease progression and failure of the humoral immune response in HIV-1 infection. FUNDING SOURCE: NIH