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Abstract
HIV-1 replication normally requires Vif-mediated neutralization of APOBEC3 antiviral enzymes. Viruses lacking Vif succumb to deamination-dependent and -independent restriction processes. Here, HIV-1 adaptation studies were leveraged to ask whether viruses with an irreparable vif deletion could develop resistance to restrictive levels of APOBEC3G. Several resistant viruses were recovered with multiple amino acid substitutions in Env, and these changes alone are sufficient to protect Vif-null viruses from APOBEC3G-dependent restriction in T cell lines. Env adaptations cause decreased fusogenicity, which results in higher levels of Gag-Pol packaging. Increased concentrations of packaged Pol in turn enable faster virus DNA replication and protection from APOBEC3G-mediated hypermutation of viral replication intermediates. Taken together, these studies reveal that a moderate decrease in one essential viral activity, namely Env-mediated fusogenicity, enables the virus to change other activities, here, Gag-Pol packaging during particle production, and thereby escape restriction by the antiviral factor APOBEC3G. We propose a new paradigm in which alterations in viral homeostasis, through compensatory small changes, constitute a general mechanism used by HIV-1 and other viral pathogens to escape innate antiviral responses and other inhibitions including antiviral drugs.
Highlights
The seven members of the human APOBEC3 (A3) protein family are DNA cytosine deaminases encoded by tandemly arranged genes on chromosome 22 [1, 2]
APOBEC3G is a virus restriction factor that blocks the replication of viral infectivity factor (Vif)-deficient HIV-1 by deamination-dependent and -independent mechanisms
Viruses often possess multiple distinct mechanisms to evade innate immune responses, and it was unknown whether HIV-1 possesses alternative mechanisms for escaping restriction by APOBEC3G
Summary
The seven members of the human APOBEC3 (A3) protein family are DNA cytosine deaminases encoded by tandemly arranged genes on chromosome 22 [1, 2] These enzymes restrict the replication of a broad number of retroviruses including HIV-1 and some DNA viruses, and inhibit the mobilization of several endogenous retroelements and retrotransposons (reviewed by [3,4,5,6]). Of seven A3 proteins, only four—A3D, A3F, A3G, and A3H (stable haplotypes only)—contribute to HIV-1 restriction in primary T cells ([7,8,9,10] and references therein) These A3s inhibit HIV-1 replication by packaging into the viral particles through an RNA-dependent mechanism and, upon entry into new target cells, physically interfering with the progression of reverse transcription and deaminating single-stranded viral cDNA cytosines to uracils (reviewed by [3,4,5]). Such mutational events can alter the function of viral components or inactivate the virus
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