Temporal analyses of virus replication, immune responses, and efficacy in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine
Temporal analyses of virus replication, immune responses, and efficacy in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine
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DOI：
10.1128/jvi.72.9.7501-7509.1998
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发表时间：
1998-09-01
影响因子：
5.4
通讯作者：
Marx, PA
中科院分区：
文献类型：
--
作者：
Connor, RI;Montefiori, DC;Marx, PA
尽管有证据表明减毒猴免疫缺陷病毒（SIV）活疫苗可以引起对致病性SIV感染的有效保护，但缺乏关于减毒SIV体内复制动力学的详细信息。在这项研究中，我们测量了16个成年恒河猴的血浆中的SIV RNA免疫与活的，减毒株的SIV（SIVmac 239 Δ nef）。为了评价疫苗病毒复制与保护作用发生之间的关系，在免疫后5、10、15或25周，每组4只动物用致病性SIVmac 251攻击。SIVmac 239 Δ nef在接种后的前几周内在免疫的猕猴中有效复制。接种后第7天，在所有动物的血浆中检测到SIV RNA，并在7至12天出现病毒血症的峰值水平（10（5）至10（7）RNA拷贝/ml）。在攻击后，在5周时攻击的所有4只动物中、在10周时攻击的4只动物中的2只动物中、在15周时攻击的4只动物中没有一只动物中以及在25周时攻击的4只动物中的1只动物中检测到SIVmac 251。用SIVmac 239 Delta nef免疫并在10周时攻击的一只动物在不存在可检测的SIVmac 251的情况下具有疾病进展的证据。虽然在5周时未达到完全保护，但与未免疫对照组相比，免疫猕猴在攻击后早期发生病毒血症一过性减少（约100倍）。攻击后两周，与对照动物相比，所有免疫猕猴的淋巴结中SIV RNA也减少。总之，这些结果表明，能够降低血浆和淋巴结中病毒载量的宿主应答早在用STVmac 239 Δ nef免疫后5周就被诱导，而更有效的保护在10至15周之间发展。在进一步的实验中，我们发现对SIVmac 251感染的抗性与SIV gp 130和p27抗原的抗体的存在无关，并且是在缺乏对主要SIVmac 251攻击储备的显著中和活性的情况下实现的。
Despite evidence that live, attenuated simian immunodeficiency virus (SIV) vaccines can elicit potent protection against pathogenic SIV infection, detailed information on the replication kinetics of attenuated SIV in vivo is lacking. In this study, we measured SIV RNA in the plasma of 16 adult rhesus macaques immunized with a live, attenuated strain of SIV (SIVmac239 Delta nef). To evaluate the relationship between replication of the vaccine virus and the onset of protection, four animals per group were challenged with pathogenic SIVmac251 at either 5, 10, 15, or 25 weeks after immunization. SIVmac239 Delta nef replicated efficiently in the immunized macaques in the first few weeks after inoculation. SIV RNA was detected in the plasma of all animals by day 7 after inoculation, and peak levels of viremia (10(5) to 10(7) RNA copies/ml) occurred by 7 to 12 days. Following challenge, SIVmac251 was detected in all of the four animals challenged at 5 weeks, in two of four challenged at 10 weeks, in none of four challenged at 15 weeks, and one of four challenged at 25 weeks. One animal immunized with SIVmac239 Delta nef and challenged at 10 weeks had evidence of disease progression in the absence of detectable SIVmac251. Although complete protection was not achieved at 5 weeks, a transient reduction in viremia (approximately 100-fold) occurred in the immunized macaques early after challenge compared to the nonimmunized controls. Two weeks after challenge, SIV RNA was also reduced in the lymph nodes of all immunized macaques compared with control animals. Taken together, these results indicate that host responses capable of reducing the viral load in plasma and lymph nodes were induced as early as 5,weeks after immunization with STVmac239 Delta nef, while more potent protection developed between 10 and 15 weeks. In further experiments, we found that resistance to SIVmac251 infection did not correlate with the presence of antibodies to SIV gp130 and p27 antigens and was achieved in the absence of significant neutralizing activity against the primary SIVmac251 challenge stock.