Developing an animal model that is close to human AIDS is always an important topic in HIV/AIDS research. Notably, the pig-tailed macaque cells do not express the TRIM5α protein restricting HIV-1 replication, and pig-tailed macaque is the only primate in Old World monkeys that can be infected by HIV-1. Pig-tailed macaques have been divided into three species: sunda pig-tailed macaques (Macaca nemestrina)，northern pig-tailed macaques (Macaca leonina) and mentawai macaques (Macaca pagensis). So far, almost all the pig-tailed macaques infected by SIV/HIV are Macaca nemestrina. Studies have shown that the interaction between restriction factors APOBEC3G/3F (A3G/A3F) and HIV/SIV-derived Vif proteins is species-specificity, indicating that A3G and A3F are key barriers for cross-species transmission of HIV-1. In recent years, it has been found that substitution of vif with that from SIVmac or SIVmne enabled persistent replication of HSIV in Macaca nemestrina. Meanwhile, a number of studies have suggested that there is a correlation between A3G and A3F mRNA expression levels in HIV-1-infected patients and their disease progression. In this dissertation, we investigated the replication abilities of vif-substituted HIV-1 (HSIV-vifmac, stHIV-1SV and HSIV-9N14) in northern pig-tailed macaque PBMCs and examined the temporal dynamic changes of A3G and A3F mRNA expression during infection. We found that the ability for HIV/HSIV to infect northern pig-tailed macaque PBMCs can be listed as follows: stHIV-1SV > HSIV-vifmac > HSIV-9N14 > HIV-1NL4-3. stHIV-1SV and HSIV-vifmac can replicate robustly in PBMCs from Macaca leonina, implying that their Vif protein has overcome the restriction of APOBEC3 effectively in macaque cells. Therefore, stHIV-1SV and HSIV-vifmac can be applied to the establishment of northern pig-tailed macaque AIDS model. In addition, we found that the expression level of A3G mRNA in PBMCs of Macaca leonina is either comparable to the A3F mRNA level or even lower than A3F mRNA expression, which is contrary to the A3G/A3F mRNA expression in human PBMCs. However, the expression levels of A3G relative to A3F mRNA levels in PBMCs from Chinese rhesus macaques are donor-dependent. The A3G and A3F relative mRNA expression levels in human PBMCs can be induced by HIV/HSIV infection. Notably, the average mRNA expression levels for both A3G and A3F in HIV/HSIV-infected human PBMCs increased about 3 times higher than uninfected PBMCs at day 6. The temporal dynamic changes in A3G mRNA expression levels and in A3F mRNA levels in HIV/HSIV-infected northern pig-tailed macaque PBMCs were consistent; however, there existed large individual variations. On the whole, A3G and A3F mRNA expression levels were upregulated in PBMCs from Macaca leonina infected by HIV, SIV and HSIV at early stage (day 1 to day 3); the A3G and A3F mRNA expression levels in stHIV-1SV and SIVmac-infected macaque PBMCs were upregulated more than that in HIV-1 and HSIV-vifmac infected macaque PBMCs. In contrast to the results in HIV/HSIV-infected human PBMCs, A3G and A3F relative mRNA expression levels changed little in HIV/HSIV-infected macaque PBMCs at day 6. Additionally, there is no correlation between p24 antigen concentrations and A3G or A3F mRNA relative expression levels during HIV/HSIV infection in PBMCs from both humans and Macaca leonina. In conclusion, our results suggest that the expression changes of A3G and A3F may influence HSIV infection of northern pig-tailed macaques and has laid a foundation for establishing novel northern pig-tailed macaque models of HSIV infection in vivo.
修改评论