Connor R I, Montefiori D C, Binley J M, Moore J P, Bonhoeffer S, Gettie A, Fenamore E A, Sheridan K E, Ho D D, Dailey P J, Marx P A
The Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York 10016, USA.
J Virol. 1998 Sep;72(9):7501-9. doi: 10.1128/JVI.72.9.7501-7509.1998.
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 (SIVmac239Deltanef). 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. SIVmac239Deltanef 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 SIVmac239Deltanef 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 SIVmac239Deltanef, 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.
尽管有证据表明减毒活猴免疫缺陷病毒（SIV）疫苗可引发针对致病性SIV感染的有效保护，但缺乏关于减毒SIV在体内复制动力学的详细信息。在本研究中，我们测量了16只接种减毒SIV株（SIVmac239Deltanef）的成年恒河猴血浆中的SIV RNA。为了评估疫苗病毒复制与保护开始之间的关系，每组4只动物在免疫后5、10、15或25周用致病性SIVmac251进行攻击。SIVmac239Deltanef在接种后的头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，病毒血症峰值水平（10^5至10^7 RNA拷贝/毫升）在7至12天出现。攻击后，在5周时攻击的4只动物中的所有动物中检测到SIVmac251，在10周时攻击的4只动物中的2只中检测到，在15周时攻击的4只动物中均未检测到，在25周时攻击的4只动物中的1只中检测到。一只接种SIVmac239Deltanef并在10周时受到攻击的动物在没有可检测到的SIVmac251的情况下有疾病进展的证据。尽管在5周时未实现完全保护，但与未免疫的对照相比，免疫的猕猴在攻击后早期病毒血症出现短暂降低（约100倍）。攻击后两周，与对照动物相比，所有免疫的猕猴淋巴结中的SIV RNA也减少。综上所述，这些结果表明，早在用SIVmac239Deltanef免疫后5周就诱导了能够降低血浆和淋巴结中病毒载量的宿主反应，而在10至15周之间发展出了更强的保护作用。在进一步的实验中，我们发现对SIVmac251感染的抗性与针对SIV gp130和p27抗原的抗体的存在无关，并且在对原发性SIVmac251攻击毒株没有明显中和活性的情况下实现。
