IFNα induces an antiviral response in cells by upregulating a range of cellular factors, some of which are known HIV restriction factors. In search of new restriction factors, Goujon et al. screened cell lines and primary cells that had varying levels of IFNα responsiveness (and subsequent HIV resistance) by transcriptional profiling. The authors identified 14 IFN-induced genes that were upregulated in responsive HIV-resistant cells; in ectopic expression experiments only one of these genes, MX2, inhibited HIV infection. Silencing of MX2 using short hairpin RNAs increased HIV infection in IFNα-treated responsive cells but had no effect in the absence of the cytokine, which indicates that MX2 makes an important contribution to IFNα-induced restriction. Further experiments revealed that MX2 reduced the levels of 2-long terminal repeat circular DNA (which is a nuclear form of reverse-transcribed HIV DNA) and integrated viral DNA, which suggests that MX2 either decreases the stability of viral replication complexes or blocks their nuclear import.
Liu et al. also showed that MX2 reduces HIV DNA integration. To determine which viral proteins are targeted by MX2, the authors passaged HIV in MX2-expressing cells until MX2-resistant viruses evolved. The viruses acquired three mutations; one of these affected residue Ala88 in the viral capsid protein, which is known to interact with the cellular protein cyclophilin A (CYPA). Silencing CYPA increased HIV replication in MX2-expressing cells and immunoprecipitation experiments showed that CYPA and MX2 interact, which suggests that CYPA is crucial for targeting MX2 to the HIV capsid. Goujon et al. also found that viruses with mutated capsids had reduced sensitivity to MX2.
This is a preview of subscription content, access via your institution
