The Restriction Factors of Human Immunodeficiency Virus

Abstract

Cellular proteins called "restriction factors" can serve as powerful blockades to HIV replication, but the virus possesses elaborate strategies to circumvent these barriers. First, we discuss general hallmarks of a restriction factor. Second, we review how the viral Vif protein protects the viral genome from lethal levels of cDNA deamination by promoting APOBEC3 protein degradation; how the viral Vpu, Env, and Nef proteins facilitate internalization and degradation of the virus-tethering protein BST-2/tetherin; and how the viral Vpx protein prevents the premature termination of reverse transcription by degrading the dNTPase SAMHD1. These HIV restriction and counter-restriction mechanisms suggest strategies for new therapeutic interventions. Restriction Factor HallmarksRestriction factors have at least four defining characteristics (see Fig. 1A). First and foremost, a restriction factor must directly and dominantly cause a significant decrease in HIV infectivity. This is often determined by cotransfecting cell lines such as HEK293 and HeLa with a molecular clone of the virus, with or without a plasmid expressing the restriction factor, and measuring the amount and infectivity of virus recovered in the cell culture medium after 1-2 days of incubation. Such assays are ideally done over a range of restriction factor expression, with the highest levels often imposing log-scale drops in viral infectivity (see Fig. 1B). This "single-cycle" assay for viral replication is useful for testing the impact of viral mutations and/or restriction factor variations.Second, if a restriction factor is a true threat to viral replication, then the predecessors of HIV invariably evolved an equally potent counter-restriction mechanism that still exists in the present day virus. For instance, titrating a counter-restriction factor into the aforementioned single-cycle infectivity experiment can result in a full recovery of viral infectivity despite the presence of an active restriction factor (Fig. 1B). Viruses lacking these various countermeasures are able to replicate in some, but not all, cell types depending on the expression level of the relevant restriction factor. Cell lines that support replication are termed "permissive," and those that do not are termed "nonpermissive." This life/death dichotomy has been elegantly exploited to identify several restriction factors and their corresponding viral antagonists.Third, because the interactions between restriction and counter-restriction factors occur through direct protein-protein interactions, the restriction factor often shows signatures of rapid evolution. In general, mutations are maintained in a population only if they confer a selective advantage. If a host species experiences iterative rounds of pathogenic pressure, altered variants of host restriction factors that are no longer susceptible to the pathogen's counteraction mechanism are selected. Over evolutionary time, this results in an overabundance of amino acid substitution mutations in these genes relative to non-amino acid...

Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

“…Viruses that persist are in a continuous "tug of war" with their host and must be able to counteract the antiviral responses continuously imposed on the virus. Among the multiple factors used by hosts to defend against viruses is the APOBEC3 family of restriction factors (46). Some retroviruses, such as HIV, simian immunodeficiency virus (SIV), and feline immunodeficiency virus (FIV), encode Vif proteins that bind APOBEC3 proteins and target them for degradation in virus-producing cells.…”

Uracil DNA glycosylase initiates degradation of HIV-1 cDNA containing misincorporated dUTP and prevents viral integration

“…Immune cells have evolved multiple ways of using uracil as a weapon against invading viruses. One well-characterized mechanism is the enzymatic deamination of cytosine in the minus strand of HIV-1 cDNA by members of the APOBEC3 subfamily (APOBEC3D, -F, -G, and -H) to generate C/G→U/A transition mutations after plus strand synthesis (43,44). This deamination mechanism leads to lethal hypermutation of the viral genome and potent restriction of viral infection, but there are conflicting reports as to whether UNG2 excision of uracils is part of the restriction mechanism (45)(46)(47).…”

APOBEC3B: Pathological consequences of an innate immune DNA mutator

“…First, many of the APOBEC3s have been described to defend against a diverse array of viral pathogens, including retroviruses, hepatitis viruses, papillomaviruses, and others. [20][21][22][23][24] Of note, APOBEC3D, F, G, and H have been shown to restrict HIV-1 replication by deaminating cDNA intermediates that normally occur during the HIV-1 life cycle. [25,26] Second, several APOBEC3s, including APOBEC3A, B, and F, have been shown to inhibit retrotransposition of L1 and Alu elements in human cells.…”