SIVmac239Infected Rhesus Monkeys Of Chinese Origin

The worldwide prevalence of human immunodeficiency virus (HIV) caused huge disaster. Unfortunately, there is no vaccine proved to be effective to protect human from HIV infection until now. After a series of failure of AIDS vaccine research, it’s well recognized that the shortage of basic science research on HIV/AIDS is the most important barrier for the development of AIDS vaccine, and the shortage of an ideal animal model limited the progression of such researchs.Since the HIV-1does not replicate in most animal species hitherto tested, including rodents and small non-human primates, SIV-HIV chimera (SHIV) has been constructed by inserting partial genome of HIV-1into SIV and applied to infect rhesus monkeys as a substitude animal model of HIV/AIDS. But recently, the reliability of this model has been doubted, since vaccines verified to be effective in this model had failed to proctect human from infection in clinical trials. So, the most popular animal model of HIV/AIDS is still the SIV infected Indian rhesus macaque, which offered us a powerful tool to understant the pathogenesis of AIDS. Howerover, this model has significant limitations compared with HIV-1infection in human, such as AIDS develops much more rapidly and the SIV plasma viral loads are as much as1000-fold higher in this model. Recently, researchers attempted to use rhesus macaques of Chinese origin (Ch Rh) for the animal model of HIV/AIDS, and their preliminary results suggested that Ch Rh may be better[2-4]. However, their use in AIDS research has been limited by less reports and shortage of knowledge about their biological characteristics. On the other hand, virus inoculum is the other critical element affected the biological characteristics of animal model. For example, the infection of a widely used isolate SIVmac251caused large individual variations[1], which made more animal cost were necessary and hampered the analysis of experiment data.In this research, standard molecular cloned SIVmac239was used to inoculate31Ch Rh by intravenous, intrarectal and intravaginal routes. These monkeys were derived from the southern of Guang-Xi province of China, where is the inhabited area of M. m. mulatta subspecie of Ch Rh. After SIV inoculation,2years follow-up results including the clinical manifestations, plasma viral loads, CD4+T cell counts, and the progression of AIDS were observed and analyzed detailedly, and pathological examinations were perfomed in biopsy lymph node and autopsy specimens. Moreover, variation of SIV in the V1/V2region of env during the progression to simian AIDS were assayed and analyzed. Finally, this model was evaluated based on their biological characteristics and the comparision with other SIV infected animal models.Results of this study including:after SIVmac239infection in Ch Rh,1)kinetics of plasma viral load is similar to HIV-1infection in human and SIV replication in other popular animal models, and the viral load values in peak and steady-stage are more closer to HIV-1infecion;2)CD4+T cells decreased continuously and gradually, and the rate of CD4+T celldecline is proportional to that of HIV-1infected humans;3) individual variations on the virological and immunological parameters are small, especillay in intravenous infected monkeys, which means less animals are needed to get statistical significant results;4) AIDS progression period is more suitable, and both the ratios of rapid progressors and conventional progressors and the speed of AIDS progression are similar to that of HIV-1infected humans, which means similar pathogenesis to HIV-1infection;5) Intrarectal and intravaginal infections are available as well as intravenous infection;6) pathological examinations showed similar changes with AIDS patients although SIVmac239is a lymphotrophic isolate.These results suggested that SIVmac239infected Ch Rh may be an optimal animal model for the research of HIV/AIDS. This study will provide important basic data for this optimal animal model and prompt its application in the pathogenesis research and vaccine development of HIV/AIDS. This study also offered us some interesting clues for futher research, such as:1) CD4+T cell count decreased later and plasma viral load was lower after intrarectal infection (P>0.05), and some animals in this group controlled the replication of SIV spontaneously, which emphasized that it’s very important to understand the immunological mechanisms in mucosal infection;2) during the progression to AIDS, high frequency mutations of V1/V2region emerged in some special sites, which cause the loss or production of potential sites for N-linked glycosylation;3) most of the variations in this study are similar to the varitions of SIVmac239in Indian rhesus monkeys, but there are some variations are very different, such as the67V→L mutation only seen in50%(2/4) of intravaginal infected animals companied with higher CD4+T cells;4) variations in most of sites accumulated during the progression of AIDS;5) no special variation in V1/V2region was found to be correlated with rapidly progression of AIDS and rapidly decline of CD4+T cells. These results are helpful for the research of mucosal immunity, virus variations and other critical topics.