Host and viral determinants of Mx2 antiretroviral activity

Busnadiego, I. et al. (2014) Host and viral determinants of Mx2 antiretroviral activity. Journal of Virology, 88(14), pp. 7738-7752. (doi: 10.1128/JVI.00214-14) (PMID:24760893) (PMCID:PMC4097781)

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Myxovirus resistance 2 (Mx2/MxB) has recently been uncovered as an effector of the anti-HIV-1 activity of type I interferons (IFNs) that inhibits HIV-1 at an early stage postinfection, after reverse transcription but prior to proviral integration into host DNA. The mechanistic details of Mx2 antiviral activity are not yet understood, but a few substitutions in the HIV-1 capsid have been shown to confer resistance to Mx2. Through a combination of in vitro evolution and unbiased mutagenesis, we further map the determinants of sensitivity to Mx2 and reveal that multiple capsid (CA) surfaces define sensitivity to Mx2. Intriguingly, we reveal an unanticipated sensitivity determinant within the C-terminal domain of capsid. We also report that Mx2s derived from multiple primate species share the capacity to potently inhibit HIV-1, whereas selected nonprimate orthologs have no such activity. Like TRIM5α, another CA targeting antiretroviral protein, primate Mx2s exhibit species-dependent variation in antiviral specificity against at least one extant virus and multiple HIV-1 capsid mutants. Using a combination of chimeric Mx2 proteins and evolution-guided approaches, we reveal that a single residue close to the N terminus that has evolved under positive selection can determine antiviral specificity. Thus, the variable N-terminal region can define the spectrum of viruses inhibited by Mx2.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Willett, Professor Brian and Preugschas, Miss Hannah and Hughes, Dr Joseph and Busnadiego, Dr Idoia and Rihn, Dr Suzannah and Wilson, Professor Sam and Boutell, Dr Chris
Authors: Busnadiego, I., Kane, M., Rihn, S. J., Preugschas, H. F., Hughes, J., Blanco-Melo, D., Strouvelle, V. P., Zang, T. M., Willett, B. J., Boutell, C., Bieniasz, P. D., and Wilson, S. J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:Journal of Virology
Publisher:American Society for Microbiology
ISSN (Online):1098-5514

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
617571Identification of a novel viral agent in feline immunodeficiency virus (FIV)-associated lymphomagenesis (ISSF Catalyst Fund)Brian WillettWellcome Trust (WELLCOME)097821/Z/11/ZMVLS III - CENTRE FOR VIRUS RESEARCH