Animal cells harbour multiple innate effector mechanisms that inhibit virus replication. For the pathogenic retrovirus human immunodeficiency virus type-1 (HIV-1), these include widely expressed restriction factors1 such as APOBEC3 proteins2, TRIM5α3, tetherin/BST24,5 and SAMHD16,7, as well as additional factors that are stimulated by type-1 interferon (IFN)8,9,10,11,12,13,14. Here, we employ both ectopic expression and gene silencing experiments to define the human dynamin-like, IFN-induced guanosine triphosphatase (GTPase), myxovirus resistance 2 (MX2 or MxB) protein, as a potent inhibitor of HIV-1 infection and as a major effector of IFNα-mediated resistance to HIV-1 infection. MX2 suppresses infection by all HIV-1 strains tested, has similar to modest effects on divergent simian immunodeficiency viruses (SIVs), and does not inhibit other retroviruses such as murine leukaemia virus (MLV). The capsid (CA) region of the viral Gag protein dictates susceptibility to MX2, and the block to infection occurs at a late post-entry step with the nuclear accumulation and chromosomal integration of nascent viral cDNA both being suppressed. Finally, human MX1 (or MxA), a closely related protein that has long been recognised as a broadly acting inhibitor of RNA/DNA viruses, including the orthomyxovirus influenza A virus15,16, does not affect HIV-1,whereas MX2 is ineffective against influenza virus. MX2 is therefore a cell-autonomous, anti-HIV-1 resistance factor whose purposeful mobilisation may represent a new therapeutic approach for the treatment of HIV/AIDS.

The ability of interferons (IFNs) to inhibit HIV-1 replication in cell culture models has long been recognized, and the therapeutic administration of IFNα to HIV-1-infected patients who are not receiving antiretroviral therapy produces a clear but transient decrease in plasma viral load. Conversely, studies of chronic HIV-1 infection in humans and SIV-infected animal models of AIDS show positive correlations between elevated plasma levels of IFNs, increased expression of IFN-stimulated genes (ISGs), biomarkers of inflammation and disease progression. In this Review, we discuss the evidence that IFNs can control HIV-1 replication in vivo and debate the controversial role of IFNs in promoting the pathological sequelae of chronic HIV-1 infection.

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In treated patients monitored by RealTime, a VL of 40-49 copies/mL and, to a lesser extent, RNA detection <40 copies/mL predict rebound >50 and >400 copies/mL independently of other recognized determinants. The goal of HAART may need to be revised to a lower cutoff than 50 copies/mL.