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

该项目涉及一些以临床为基础的研究，旨在描绘人类免疫缺陷病毒(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，在接种破伤风类毒素疫苗后，HIV-1感染患者在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。与免疫前相比，免疫后大多数患者的外周血单核细胞更容易分离出HIV。我们还证明了在破伤风免疫后，正常志愿者的PBMCs对HIV感染的易感性增加。对血浆中病毒爆发的系统发育分析在大多数情况下反映了病毒复制的非特异性增加，继而是易感CD4T细胞池的扩大。一个例外情况是，免疫有利于M嗜性(利用CCR5)而不是T嗜性(利用CXCR4)病毒的扩展。在三名患者中，有一名患者的数据表明，免疫激活导致了从潜伏感染细胞诱导的病毒出现在血浆中。对25例HIV-1感染者和10例非感染者的全血标本中CCR5和CXCR4的表达进行了横断面研究。我们发现，在HIV-1感染和未感染的个体中，共受体的表达与体内细胞激活水平有关，CXCR4主要表达在静止的(HLA-DR-)T细胞上，而CCR5主要表达在激活的(HLA-DR)T细胞上。CD4T细胞表面CXCR4的低表达和CCR5的高表达与疾病进展有关。对23例各种形式的急、慢性丝虫病患者和10例血库对照进行了研究。我们发现，与对照组相比，丝虫病患者未经刺激的PBMCs的易感性略有增加。对6例丝虫病患者治疗前后的感染易感性进行了评估。在六分之三的患者中，抗丝虫病治疗显著降低了感染的易感性，而在另外三名患者中，这一点没有变化。-免疫激活；艾滋病毒；病毒准种；艾滋病毒共同受体；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