Structural And Functional Insights Into The HIV Restriction Factor-SAMHD1 And MxB

SAMHD1 and MxB,two anti-HIV restriction factors,are recently discovered which consistently establish barriers against HIV virus.SAMHD1 can block the replication of HIV-1 virus effectively in multiple modes that mainly include its dNTPase and RNase.To be specific,its dNTPase activity prevents the HIV-1 infection in immune cells by depleting the cellular dNTP pool available for viral replication,while the RNase activity of SAMHD1 is responsible for inhibiting HIV-1 infection by directly degrading the HIV-1 DNA or RNA.Nevertheless,HIV-2 and related SIVs viral proteins Vpx and Vpr can hijack a host DDB1/DCAF1-dependent E3 ubiquitin ligase for SAMHD1 ubiquitination and proteasomal degradation,thus,eliminating the inhibition of SAMHD1.MxB acts as a novel restriction factor with antiviral activity against a range of HIV-1 and other retroviruses mainly by targeting the viral capsid and inhibiting the uncoating process after reverse transcription but prior to integration.However,the antiviral mechanism of SAMHD1 that primarily depend on its dNTPase or its RNase activity is still controversial.In addition,MxB restricts HIV-1 through an ambiguous mechanism and it is controversial as to which step the antiviral function of MxB occurs downstream of HIV-1 reverse transcription.Therefore,we elucidated the mechanism of antiviral and cellular functions of SAMHD1 and MxB through a series of Structural Biology,Biochemistry,Molecular Biology and Cell Biology methods.It can be stated as follows:1.Mechanism of antiviral and cellular functions of SAMHD1.(1)We found that the interface between the A and C subunits is essential for the tetramer formation and d NTPase of SAMHD1;(2)We made a deep exploration about the structure of SAMHD1 with its RNase activity;(3)SIVmac/SIVrcm Vpx could hijack a host DDB1/DCAF1-dependent E3 ubiquitin ligase for SAMHD1 ubiquitination and proteasomal degradation;(4)For the first time,we found SAMHD1 HD domain could target viral capsid directly and discovered the recognition pattern of SAMHD1 with CA had a close relationship with TRIM5? and MxB;2.Mechanism of anti-virus function of MxB.(1)MxB interacts directly with capsid through the first 83 amino acids but not the G domain and stalk,and shows no appreciable affinity for CA oligomers but binds to a higher-order assembled CA lattice.(2)We proposed a novel model,in which MxB dimers form higher-order oligomers that restrict retroviral replication by binding to the viral capsid.Our research works elucidated the role of SAMHD1 and MxB particularly in the fight against HIV.Moreover,it establishes a framework for understanding the antiviral mechanism of SAMHD1 and MxB,and provides invaluable information for drug development,prevention and treatment of HIV.