Journal
JOURNAL OF VIROLOGY
Volume 89, Issue 16, Pages 8599-8610Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00753-15
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Funding
- NIH [R01 AI087390, R21 AI102824, R56 AI108432]
- National Institutes of Health [T32 AI07501]
- ANRS
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI087390, R21AI102824, T32AI007501, R56AI108432] Funding Source: NIH RePORTER
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The interferon alpha (IFN-alpha)-inducible restriction factor MxB blocks HIV-1 infection after reverse transcription but prior to integration. Fate-of-capsid experiments have correlated the ability of MxB to block HIV-1 infection with stabilization of viral cores during infection. We previously demonstrated that HIV-1 restriction by MxB requires capsid binding and oligomerization. Deletion and gain-of-function experiments have mapped the HIV-1 restriction ability of MxB to its N-terminal 25 amino acids. This report reveals that the N-terminal 25 amino acids of MxB exhibit two separate functions: (i) the ability of MxB to bind to HIV-1 capsid and (ii) the nuclear localization signal of MxB, which is important for the ability of MxB to shuttle into the nucleus. To understand whether MxB restriction of HIV-1 requires capsid binding and/or nuclear localization, we genetically separated these two functions and evaluated their contributions to restriction. Our experiments demonstrated that the (RRR13)-R-11 motif is important for the ability of MxB to bind capsid and to restrict HIV-1 infection. These experiments suggested that capsid binding is necessary for the ability of MxB to block HIV-1 infection. Separately from the capsid binding function of MxB, we found that residues (KY21)-K-20 regulate the ability of the N-terminal 25 amino acids of MxB to function as a nuclear localization signal; however, the ability of the N-terminal 25 amino acids to function as a nuclear localization signal was not required for restriction. IMPORTANCE MxB/Mx2 blocks HIV-1 infection in cells from the immune system. MxB blocks infection by preventing the uncoating process of HIV-1. The ability of MxB to block HIV-1 infection requires that MxB binds to the HIV-1 core by using its N-terminal domain. The present study shows that MxB uses residues (RRR13)-R-11 to bind to the HIV-1 core during infection and that these residues are required for the ability of MxB to block HIV-1 infection. We also found that residues (KY21)-K-20 constitute a nuclear localization signal that is not required for the ability of MxB to block HIV-1 infection.
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