An Association Study Of SAMHD1 And APOBEC3G Alleles With HIV-2_ROD And SIVmac239 Infection In Chinese Rhesus Macaques

Host restriction factor is an important factor in the determination of susceptibility and developing speed of disease, and it is one of the key factors in the inhibition of viral replication on the aspect of innate immunity, humoral immunity, and cellular immunity. Previous study in our group have investigated the effects of TRIM5α, a host restrictive factor, suggesting that TFP339-341 ΔΔQ is a variant driving differences in HIV-2ROD replication among Chiese rhesus macaques. The TRIM5 alleles with protective TFP could restrict HIV-2 infection, but the result showed a conflict that some alleles with TFP were in a high viral load, suggesting that the HIV-2ROD replication in vivo is affected by multiple host factors. Research has show that,SAMHD1 and APOBEC3 G are important factor in the determination of susceptibility and developing speed of disease, and the study in SAMHD1 and APOBEC3 G of HIV animal models of Chinese rhesus is still rare.In this study, we base on clear genetic background of TRIM5α,and try to find the correlation between the polymorphism identification of SAMHD1 and APOBEC3 G and the viral load of HIV-2/SIV in Chinese rhesus monkey. The results are as follows:There’re 18 kinds of haplotypes and 4 SNPs was found in SAMHD1 of the group. SNPs include T168 C, A528 G, A1125 G, T320 C. T320 C is synonymous mutations, the other three non-synonymous mutations. In viral load correlation analysis, We discovered that a non-synonymous mutation T320 C is associated with the anti-SIVmac239 activity of SAMHD1 in Chinese rhesus macaques. Chinese rhesus macaque PBMCs that were TC heterozygous for the T320 C allele had much lower viral loads than those that were CC homozygous for the T320 C allele at 5 days post-infection(P<0.05). We also found that a synonymous mutation T168 C is associated with HIV-2 replication in Chinese rhesus macaques. PBMCs that were CC homozygous for the T168 C allele were significantly more resistant than those that were TT homozygotes at 3, 5, and 7 d post-infection(P<0.05). In contrast to the HIV-2ROD infections, PBMCs that were CC homozygous for the T168 C allele were more susceptible to SIVmac239 infection than those that were TT homozygotes, although the difference was not significant. Furthermore, we also determined whether the haplotypes in SAMHD1 affected HIV-2ROD or SIVmac239 replication in rhesus macaques and cynomolgus macaques. The results suggested that the haplotypes of the SNPs in the SAMHD1 gene were not associated with HIV-2ROD or SIVmac239 replication in these two species.In A3 G gene has been identified novel transcripts KU058147. New transcript exons coding regions were identified with 27 SNPs, including 20 non-synonymous mutations and 7 synonymous mutations. Of which 10 SNPs newly discovered and 17 had been reported before. 70 LR + 141 D genotype is a rare genotype of which the frequency is 5.71%.We found that F82F(T246C), E88K(G262A), and G212D(A635G) were significantly associated with the anti-HIV-2ROD activity of A3 G. PBMCs that were C/C homozygous for T246 C allele had much lower viral loads than those that were T/T homozygous allele at 3 and 5 days post-infection(p <0.05), while PBMCs that were G/G homozygous for G262 A allele had much lower viral loads than those that were A/A homozygous allele at 3 and 5 days post-infection(p <0.05). The synonymous mutation F82 F that can affect the HIV-2ROD replication is because that F82 F and E88 K are in strong linkage disequilibrium(LD) in all populations(r2= 0.65), indicating that G/G allele in E88 K may protect Chinese rhesus macaques from HIV-2ROD infection. In addition, another non-synonymous mutation G212D(A635G) was also associated with HIV-2 replication in Chinese rhesus macaques. PBMCs expressing A/A homozygous for G212 D were significantly more resistant than those that were G/G homozygous and G/A heterozygous(p <0.05) and specially at 3 days and 7days, A/A homozygous showed extremely significant affection at viral load(p <0.01).This study showed that SAMHD1 and APOBEC3 G gene polymorphisms affect viral load. The experimental animal model should be genotyped for the further HIV disease mechanism research.