The Roles Of Several Major Restriction Factors On HIV-1 Replication In Northern Pig-tailed Macaques

The infection rate and incidence of AIDS have been on the rise in recent years.The lack of animal model of HIV-1 direct infection is one of the key bottlenecks to cure AIDS.Our laboratory confirmed that Pig-tailed Macaques is a potential AIDS model animal in previous studies,and successfully infected Northern Pig-tailed Macaques（NPMs）with three kinds of HIV-1 virus:HIV-1_NL4-3,HIV-1_NL4-R3A,st HIV-1sv and one SIV virus:SIV_mac239,and established the related HIV-1/SIV animal model.Among them,HIV-1_NL4-3,HIV-1_NL4-R3A and st HIV-1sv infected with NPMs were non-pathogenic models with low level of virus replication,while SIV_mac239 infected with NPMs was an AIDS model with high level of virus replication.At present,most studies believe that IFN-I,mainly IFN-α,and its induced antiviral genes（host restriction factors）play an important role in inhibiting viral replication.In this study,in order to find out the reasons for the low level of HIV-1 replication in NPMs,especially in the chronic infection stage,we first used HIV-1_NL4-3 and SIV_mac239 infected NPMs as the research objects,and compared the characteristics of viral replication,IFN-αand its induced limiting factor expression in each tissue of the chronic stage of these two models.We found that viral RNA and DNA could be detected in all tissues of the chronic phase of HIV-1 or SIV_mac239 infected NPMs.The copies of viral DNA and RNA in the lymph nodes and spleen of SIV_mac239 infected NPMs were significantly higher than those in HIV-1_NL4-3 infected tissues.Furthermore,IFN-αexpression was higher in the lymph nodes and spleen of HIV-1-infected NPMs than in SIV_mac239 infected tissues.In addition,Tetherin and MX2,the HIV-1 restriction factors induced by IFN-α,as well as the inflammatory factors IFN-γ,TNF-αand IL-6 were also expressed at higher levels in the tissues of HIV-1-infected NPMs.Therefore,these results suggest that,unlike SIV_mac239 infection,HIV-1 infection can induce high expression of IFN-αand higher antiviral status,which may be one of the reasons why HIV-1 cannot replicate at high levels and develop into AIDS in NPMs.stHIV-1sv is an HIV-1-derived strain that replaces the SIV_mac239 vif gene,which is widely believed to antagonize the APOBEC3G（A3G）and APOBEC3F（A3F）restriction.Thus,the virus replicates at a higher level in NPMs than the HIV-1 strain.However,our previous study found that st HIV-1sv replication was also inhibited in the chronic infection stage of NPMs.In order to find out the possible molecular mechanism,in another part of this paper,we used HIV-1_NL4-3 as negative control and SIV_mac239 as positive control to analyze the relationship between the expression of A3G and A3F and the change of virus sequence after st HIV-1sv infection of NPMs.We found that in the tissues infected with these three viruses in NPMs,after HIV-1_NL4-3 infection,the expression of A3G and A3F was the highest,followed by st HIV-1sv,and SIV_mac239.In order to explore the effect of A3G and A3F on the virus sequence,we sequenced the env region of viruses in different tissues.It was found that the mutation of env region in HIV-1 infected tissues was much higher than that of SIV_mac239.In the tissues of st HIV-1sv infected NPMs,the number of env mutations was significantly different among different tissues.Among them,the number of env mutations in the lymph nodes of st HIV-1sv infected NPMs was higher than that of SIV_mac239.The results were positively correlated with the m RNA expression levels of A3G and A3F.These results indicated that st HIV-1sv had tissue-specific antagonism against vif.Moreover,st HIV-1sv could not antagonize A3G and A3F as well as SIV_mac239,which might be one of the reasons why st HIV-1sv could not replicate at a sustained high level in NPMs.In conclusion,this study compared the three HIV-1 virus infection model with SIV_mac239 infection model,and analyzed the role and possible mechanism of IFN-αand its induced host resteiction factor in inhibiting HIV-1 replication,which provides a theoretical basis for improving the HIV-1-infected model of NPMs.