The Interferon-Inducible MxB Protein Inhibits HIV-1 Infection

Abstract

The interferon-inducible myxovirus resistance (Mx) proteins play important roles in combating a wide range of virus infections. MxA inhibits many RNA and DNA viruses, whereas the antiviral activity of MxB is less well established. We find that human MxB inhibits HIV-1 infection by reducing the level of integrated viral DNA. Passaging HIV-1 through MxB-expressing cells allowed the evolution of a mutant virus that escapes MxB restriction. HIV-1 escapes MxB restriction by mutating the alanine residue at position 88 in the viral capsid protein (CA), with a consequent loss of CA interaction with the host peptidylprolyl isomerase cyclophilin A (CypA), suggesting a role for CypA in MxB restriction. Consistent with this, MxB associates with CypA, and shRNA-mediated CypA depletion or cyclosporine A treatment resulted in the loss of MxB inhibition of HIV-1. Taken together, we conclude that human MxB protein inhibits HIV-1 DNA integration by a CypA-dependent mechanism.

MxB Is Not Responsible for the Blocking of HIV-1 Infection Observed in Alpha Interferon-Treated Cells

“…These experiments suggested that MxB does not contribute to the ability of IFN-␣-treated cells to block HIV-1 infection. This is in agreement with the following reported findings suggesting that MxB is not the restriction factor responsible for the block to HIV-1 observed in IFN-␣-treated human cells: (i) MxB is an HIV-1 restriction factor that blocks HIV-1 infection after reverse transcription (9,22,23,27,29), and (ii) treatment of human cells with IFN-␣ imposes a restriction on HIV-1 before the occurrence of reverse transcription (35). Next, we investigated the HIV-1 life cycle stage at which the block imposed by IFN-␣-treated THP-1 cells occurs.…”

“…Genetic evidence suggested that the HIV-1 capsid is the determinant for the ability of MxB to block HIV-1 infection (9,22,23). In agreement with these findings, we recently demonstrated that MxB binds to the HIV-1 capsid and correlated the ability of MxB to block HIV-1 infection with inhibition of uncoating (24).…”

“…Contrary to MxB, the antiviral role of MxA has been extensively studied for viruses including influenza virus (1, 12-15), tick-borne Thogoto virus (16), African swine fever virus (17), hepatitis B virus (18), and La Crosse virus (19,20). The antiviral activity of the long form of MxB was recently described (9, 21-23); these investigations led to the discovery that the IFN-␣-inducible protein MxB blocks HIV-1 infection.Genetic evidence suggested that the HIV-1 capsid is the determinant for the ability of MxB to block HIV-1 infection (9,22,23). In agreement with these findings, we recently demonstrated that MxB binds to the HIV-1 capsid and correlated the ability of MxB to block HIV-1 infection with inhibition of uncoating (24).…”

“…Contrary to MxB, the antiviral role of MxA has been extensively studied for viruses including influenza virus (1,(12)(13)(14)(15), tick-borne Thogoto virus (16), African swine fever virus (17), hepatitis B virus (18), and La Crosse virus (19,20). The antiviral activity of the long form of MxB was recently described (9,(21)(22)(23); these investigations led to the discovery that the IFN-␣-inducible protein MxB blocks HIV-1 infection.…”

“…The myxovirus B (MxB) gene was originally cloned from a human glioblastoma cell line treated with alpha interferon (IFN-␣) (4,5). MxB as well as the related protein MxA belong to the dynamin-like family of proteins, which have diverse functions ranging from vesicle transport to antiviral activity (1,(6)(7)(8)(9)(10)(11). The most studied dynamin-like protein that exhibits antiviral activity is MxA (1,2).…”