Host and viral determinants of Mx2 antiretroviral activity.
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. Importance: Type I interferons (IFNs) inhibit the replication of most mammalian viruses. IFN stimulation upregulates hundreds of different IFN-stimulated genes (ISGs), but it is often unclear which ISGs are responsible for inhibition of a given virus. Recently, Mx2 was identified as an ISG that contributes to the inhibition of HIV-1 replication by type I IFN. Thus, Mx2 might inhibit HIV-1 replication in patients, and this inhibitory action might have therapeutic potential. The mechanistic details of how Mx2 inhibits HIV-1 are currently unclear, but the HIV-1 capsid protein is the likely viral target. Here, we determine the regions of capsid that specify sensitivity to Mx2. We demonstrate that Mx2 from multiple primates can inhibit HIV-1, whereas Mx2 from other mammals (dogs and sheep) cannot. We also show that primate variants of Mx2 differ in the spectrum of lentiviruses they inhibit and that a single residue in Mx2 can determine this antiviral specificity.
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, United Kingdom.
Idoia
I
Busnadiego
Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, USA Laboratory of Retrovirology, The Rockefeller University, New York, New York, USA.
Melissa
M
Kane
Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, USA Laboratory of Retrovirology, The Rockefeller University, New York, New York, USA.
Suzannah J
SJ
Rihn
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, United Kingdom.
Hannah F
HF
Preugschas
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, United Kingdom.
Joseph
J
Hughes
Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, USA Laboratory of Retrovirology, The Rockefeller University, New York, New York, USA.
Daniel
D
Blanco-Melo
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, United Kingdom.
Victoria P
VP
Strouvelle
Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, USA Laboratory of Retrovirology, The Rockefeller University, New York, New York, USA Howard Hughes Medical Institute, Aaron Diamond AIDS Research Center, New York, New York, USA.
Trinity M
TM
Zang
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, United Kingdom.
Brian J
BJ
Willett
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, United Kingdom.
Chris
C
Boutell
Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, USA Laboratory of Retrovirology, The Rockefeller University, New York, New York, USA Howard Hughes Medical Institute, Aaron Diamond AIDS Research Center, New York, New York, USA pbienias@adarc.org sam.wilson@glasgow.ac.uk.
Paul D
PD
Bieniasz
MRC-University of Glasgow Centre for Virus Research, Institute of Infection, Inflammation and Immunity, University of Glasgow, Glasgow, United Kingdom pbienias@adarc.org sam.wilson@glasgow.ac.uk.
Sam J
SJ
Wilson
D000818:Animals; D004252:DNA Mutational Analysis; D019143:Evolution, Molecular; D016655:HIV Core Protein p24 / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016296:Mutagenesis; D064547:Myxovirus Resistance Proteins / Q000276:immunology*
D016655:HIV Core Protein p24; C579068:MX2 protein, human; D064547:Myxovirus Resistance Proteins