NATURAL HISTORY OF SIVMAC BK28 & H824 INFECTION IN MACACA NEMESTRINA

在这个项目中，我们试图通过使用两个密切相关的SIV挑战毒株来识别疾病进展的早期预测因素，这两个毒株的致病力在M.Mulatta中被确定为明显不同。这些分子克隆的使用提供了独特的机会来模拟艾滋病的快速和缓慢进展，同时使用分子定义的病毒。病毒和免疫的特征都在进行中。四只动物感染了SIVmacH824或BK28。至少每月进行一次病毒载量测量，H824被确定为恒河猴中更具致病性的病毒，其产生的病毒载量在20周内始终高于BK28产生的病毒载量1-2倍。感染H824的一只动物在感染19周后被安乐死。剩下的三只动物的病毒载量，无论接种何种疫苗，都下降到了无法检测的水平。尽管病毒载量有所下降，但其余感染H824的动物在感染后40周发展为艾滋病，并在58周因类似艾滋病的症状而被安乐死。这两只感染BK28的动物继续茁壮成长，尽管它们确实表现出CD4的下降。在第16周进行细胞因子产生细胞的计数；结果表明，尽管不同克隆感染的动物之间没有显著差异，但仍能诱导出干扰素阳性的CD4和CD8细胞。有趣的是，产生干扰素的细胞的峰值数量与病毒载量的峰值同步出现。我们在感染过程中继续进行这些检测，并加入额外的细胞因子和激活标记，以更好地检查细胞因子反应。我们检测了血浆中RANTES的水平，发现尽管病毒载量下降，BK28感染的动物仍保持着RANTES的表达。在一只H824感染的动物存活了58周后，RANTES水平在病毒载量下降后下降。这些结果有力地支持了根结线虫可能存在不同致病机制的假说。未来的项目将纳入这项研究中获得的信息，以开发针对SIV和HIV引起的疾病的有效疗法。

In this project we seek to identify early predictors of disease progression in M. nemestrina through the use of two closely related SIV challenge strains that differ markedly in their pathogenicity as determined in M. mulatta. The use of these molecular clones affords the unique opportunity to model fast and slow progression to AIDS while using molecularly defined viruses. Both viral and immune characterizations are being performed. Four animals were infected with either SIVmacH824 or BK28. Viral load measurements were taken at least monthly and H824, determined to be the more pathogenic virus in rhesus macaques, produced a viral load that was consistently 1-2 logs higher than the viral load produced by BK28 through week 20. One animal infected with H824 was euthanized at 19 weeks postinfection. The viral loads in the three remaining animals, regardless of inoculum, declined to undetectable levels. Despite this decline in viral load, the remaining H824-infected animal progressed to AIDS at 40 weeks postinfection and was euthanized at 58 weeks due to AIDS-like symptoms. The two BK28-infected animals continue to thrive although they do demonstrate CD4 decline. Enumeration of cytokine-producing cells was performed through week 16; the results demonstrated the induction of IFN(-positive CD4+ and CD8+ cells, although there were no significant differences between animals infected with different clones. Interestingly, peak numbers of IFN(-producing cells occurred synchronously with peak viral load. We are continuing these assays throughout the course of infection and are incorporating additional cytokine and activation markers to better examine the cytokine response. We examined plasma levels of RANTES and found that expression was maintained in BK28-infected animals despite decline of viral load. RANTES levels dropped subsequent to the drop in viral load in the one H824-infected animal that survived 58 weeks. These results strongly support the hypothesis that there would be a differential pathogenesis in M. nemestrina. Future projects will incorporate information obtained in this study to develop effective therapies for SIV- and HIV-induced disease.