Abstract
Mammals have developed clever adaptive and innate immune defense mechanisms to protect against invading bacterial and viral pathogens. Human innate immunity is continuously evolving to expand the repertoire of restriction factors and one such family of intrinsic restriction factors is the APOBEC3 (A3) family of cytidine deaminases. The coordinated expression of seven members of the A3 family of cytidine deaminases provides intrinsic immunity against numerous foreign infectious agents and protects the host from exogenous retroviruses and endogenous retroelements. Four members of the A3 proteins—A3G, A3F, A3H, and A3D—restrict HIV-1 in the absence of virion infectivity factor (Vif); their incorporation into progeny virions is a prerequisite for cytidine deaminase-dependent and -independent activities that inhibit viral replication in the host target cell. HIV-1 encodes Vif, an accessory protein that antagonizes A3 proteins by targeting them for polyubiquitination and subsequent proteasomal degradation in the virus producing cells. In this review, we summarize our current understanding of the role of human A3 proteins as barriers against HIV-1 infection, how Vif overcomes their antiviral activity, and highlight recent structural and functional insights into A3-mediated restriction of lentiviruses.
Highlights
To fight against invading bacterial and viral pathogens, eukaryotic organisms have developed effective cellular innate and adaptive immunity such as humoral and T cell-mediated immune responses, and intrinsic immunity, whereby expression of endogenous host restriction factors provides a first line of cellular defense against infections
As discussed later, the recently determined structure of an A3FCTD -virion infectivity factor (Vif)-core binding factor β (CBFβ) complex clearly showed that some A3F determinants that were predicted to be important for interaction with Vif do not interact with Vif, but instead interact with CBFβ [123]
These results suggested that a similar structural interface in A3F, A3C, and A3D is critical for interaction with HIV-1 Vif
Summary
To fight against invading bacterial and viral pathogens, eukaryotic organisms have developed effective cellular innate and adaptive immunity such as humoral and T cell-mediated immune responses, and intrinsic immunity, whereby expression of endogenous host restriction factors provides a first line of cellular defense against infections. HIV-1 replication in the absence of the virally encoded accessory protein, virion infectivity factor, Vif (Figure 2a) [26]. It is established that they all induce dC-to-dU deamination in the minus strand DNA of lentiviruses during reverse transcription, which results in G-to-A substitutions in the plus-strand DNA, resulting in missense and stop-codon mutations that block viral replication [29,30,31,32]. This phenomenon of excess G-to-A mutations was initially described in avian spleen necrosis virus (a gammaretrovirus) and referred to as G-to-A hypermutation [33]. X3-7 H x E x5 W F x16-20 S W ST P C x2 C x6 F x8 L x5 R L Y x8-11 L x2 L x8-12 x M x3-4
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