The Molecular Mechanism Of Host Factors On Modulating HIV-1 Infection

Highly active anti-retroviral therapy(HAART)can efficiently decrease the viral load in blood,reduce risk of progression to AIDS and prolong life-span of infected patients.However,HAART can not eliminate latently/persistently infected viruses.HIV-1 reservoir formed by latently infected cells represents one of the major obstacles for viral clearance or functional cure of viral infection.A multitude of molecular mechanisms can silence HIV-1 gene expression and replication.Transcription silence of HIV－1 LTR is the key to establish and maintain viral latency,which can be mediated by disorder of transcriptional factors or epigenetic modification.For better understanding the molecular mechanism of HIV-1 latency,host proteins,which can modulate HIV-1 infection,were screened by analysis of several genomics in our preliminary work.Among them,SAFB1(Scaffold Attachment Factor B1)and RBMX(RNA Binding Motif Protein,X-Linked)interact with each other,and both can associate with DNA/RNA or chromatin in turn regulate transcription of genes.In our research,we analyzed the anti-HIV mechanisms of the two host proteins and found that the both can repress transcription of HIV-1-LTR-driven.proviral DNAand maintain HIV-1 latency.1)Host factor SAFB1 inhibits HIV-1 transcription and maintains HIV-1 latency by impeding phosphorylation of RNA polymerase ⅡHere,we reported that SAFB1 inhibited HIV-1 infection in primary CD4+ T cells.Further analysis showed HIV-1 transcriptional initial and elongation as well as tat-driven LTR activity were repressed by SAFB1.SAFB1 can bind to HIV-1 LTR,which may be mediated by histone H3.SAFB1 bounded to RNA polymerase Ⅱ in nucleotide independent way and impeded phosphorylation of RNAP Ⅱ,as well as RNAP Ⅱenrichment on HIV－1 DNA.The C-terminal R/G-rich domian was critical for the inhibitory role of SAFB1.Moreover,SAFB1 depletion increased reactivation of provirus in HIV-1 latently infected CD4+ T cell model.Those results reveal a key role of SAFB1 in suppressing HIV-1 infection and regulating viral latency.2)Host factor RBMX suppresses HIV-1 transcription and modulates HVI-1 latencyRBMX has a RNA binding domain and functions in pre-mRNA alternative splicing and regulation of gene transcription.Here,we reported that RBMX knockdown significantly enhanced HIV-1 infection in CD4+ T cells.Further analysis showed transcriptional elongation was promoted with inadequate RBMX,thus LTR-driven transcription was strengthened.The SRR domain and TRR domain of RBMX were need for the anti-HIV activity.Moreover,RBMX depletion promoted reactivation of latently infection HIV-1 in CD4+ T cells.Further analysis showed RBMX and SAFB1 inhibits HIV-1 transcription respectively.Those data indicate a key role of RBMX in repressing HIV-1 infection and modulating viral latency.Overall,our researches reveal the role of host factor SAFB1 and RBMX in maintaining HIV-1 latency by repressing transcription of HIV-1 proviral DNA,which highlights the understanding for HIV-1 latency.Further screening and analysis will be benefit for enlarging our knowledge about viral latency and development of effective strategy for eradicating latently infected viruses.