ROLE OF EXOGENOUS ACTIVATION OF THE IMMUNE SYSTEM IN THE PATHOGENESIS OF HIV DIS

该项目涉及若干临床研究，旨在阐明人体免疫缺陷病毒（艾滋病毒）感染的致病机制以及免疫激活在疾病传播和免疫系统破坏中的作用。我们已经证明，破伤风类毒素加强接种后，HIV-1感染患者免疫后血浆病毒血症一过性增加，前病毒负荷增加，淋巴结内病毒增加。免疫后比免疫前更容易从大多数患者的PBMC中分离出HIV。我们还证明了破伤风免疫接种后，正常志愿者的PBMC对HIV感染的易感性增强。在大多数情况下，血浆中病毒爆发的系统发育分析反映了病毒复制的非特异性增加，继发于易感CD 4 + T细胞的扩增池。一个例外是在一名患者中，其中免疫接种有利于M嗜性（利用CCR 5）超过T嗜性（利用CXCR 4）病毒的扩增。在三名患者中的一名中，数据表明免疫激活导致从潜伏感染细胞诱导的病毒在血浆中出现。进行了一项横断面研究，评估了从25名HIV-1感染者和10名未感染者采集的全血样品中CCR 5和CXCR 4的表达。我们发现，在HIV-1感染和未感染的个体中，共受体表达与体内细胞活化水平相关，CXCR 4主要在静止（HLA-DR -）T细胞上表达，CCR 5主要在活化（HLA-DR+）T细胞上表达。CD 4 + T细胞上CXCR 4的低表达和CCR 5的高表达与疾病进展相关。23个人与各种形式的急性和慢性丝虫病和10个血库对照进行了研究。我们发现，与对照组相比，从丝虫病患者中提取的未经刺激的PBMC的易感性略有增加。在6例丝虫病患者中，评估了丝虫治疗前后的感染易感性。在6名患者中，有3名患者的抗丝虫治疗显著降低了感染的易感性，而在其他3名患者中，这种易感性没有变化。- 免疫激活; HIV;病毒准种; HIV辅助受体;丝虫病-人类受试者

This project involves a number of clinically based studies directed at delineating the pathogenic mechanisms of human immunodeficiency virus (HIV) infection and the role of immune activation in the propagation of disease and destruction of the immune system. We have demonstrated that, after tetanus toxoid booster inoculation, HIV-1 infected patients had transient increases in plasma viremia after immunization, increases in proviral burden, and increased virus within lymph nodes. HIV was more easily isolated from PBMCs from the majority of patients after immunization than before immunization. We also demonstrated an enhanced susceptibility of PBMCs to HIV infection in normal volunteers after tetanus immunization. Phylogenetic analysis of the viral bursts within plasma in most cases reflected a non-specific increase in viral replication, secondary to an expanded pool of susceptible CD4+ T cells. An exception to this was in a patient in which immunization favored the expansion of M-tropic (CCR5 utilizing) over T-tropic(CXCR4-utilizing) viruses. In one of three patients the data suggested that immune activation resulted in the appearance in plasma of virus induced from latently infected cells. A cross-sectional study was performed which evaluated the expression of CCR5 and CXCR4 in whole blood samples taken from 25 HIV-1-infected and 10 uninfected individuals. We found that co- receptor expression correlated with the level of cellular activation in vivo in both HIV-1-infected and uninfected individuals, with CXCR4 being expressed predominantly on quiescent (HLA-DR -)T cells and CCR5 being expressed predominantly on activated (HLA-DR+) T cells. Lower expression of CXCR4 and higher expression of CCR5 on CD4+ T cells correlated with advancing disease. Twenty-three individuals with various forms of acute and chronic filariasis and 10 blood bank controls were studied. We found a modest increase in susceptibility of unstimulated PBMCs taken from filariasis patients in comparison to controls. In 6 patients with filariasis, the susceptibility to infection was evaluated pre- and post-filaria treatment. In three out of six patients, anti-filarial treatment significantly decreased susceptibility to infection, whereas in the other three, it was unchanged. - Immune activation; HIV; viral quasispecies; HIV co- receptor; filariasis - Human Subjects