Examination of the APOBEC3 Barrier to Cross Species Transmission of Primate Lentiviruses

The transmission of viruses from animal hosts into humans have led to the emergence of several diseases. Usually these cross-species transmissions are blocked by host restriction factors, which are proteins that can block virus replication at a specific step. In the natural virus host, the restriction factor activity is usually suppressed by a viral antagonist protein, but this is not the case for restriction factors from an unnatural host. However, due to ongoing viral evolution, sometimes the viral antagonist can evolve to suppress restriction factors in a new host, enabling cross-species transmission. Here we examine the classical case of this paradigm by reviewing research on APOBEC3 restriction factors and how they can suppress human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). APOBEC3 enzymes are single-stranded DNA cytidine deaminases that can induce mutagenesis of proviral DNA by catalyzing the conversion of cytidine to promutagenic uridine on single-stranded viral (−)DNA if they escape the HIV/SIV antagonist protein, Vif. APOBEC3 degradation is induced by Vif through the proteasome pathway. SIV has been transmitted between Old World Monkeys and to hominids. Here we examine the adaptations that enabled such events and the ongoing impact of the APOBEC3-Vif interface on HIV in humans.

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Host Restriction Factors and Human Immunodeficiency Virus (HIV-1): A Dynamic Interplay Involving All Phases of the Viral Life Cycle

Current HIV Research ◽

10.2174/1570162x16666180817115830 ◽

2018 ◽

Vol 16 (3) ◽

pp. 184-207 ◽

Cited By ~ 9

Author(s):

Vanessa D`Urbano ◽

Elisa De Crignis ◽

Maria Carla Re

Keyword(s):

Mammalian Cells ◽

Viral Evolution ◽

Type I ◽

Restriction Factors ◽

Host Restriction ◽

Host Restriction Factors ◽

Immunodeficiency Virus ◽

Lentiviral Infection ◽

Specific Proteins ◽

Hiv 1

Mammalian cells have evolved several mechanisms to prevent or block lentiviral infection and spread. Among the innate immune mechanisms, the signaling cascade triggered by type I interferon (IFN) plays a pivotal role in limiting the burden of HIV-1. In the presence of IFN, human cells upregulate the expression of a number of genes, referred to as IFN-stimulated genes (ISGs), many of them acting as antiviral restriction factors (RFs). RFs are dominant proteins that target different essential steps of the viral cycle, thereby providing an early line of defense against the virus. The identification and characterization of RFs have provided unique insights into the molecular biology of HIV-1, further revealing the complex host-pathogen interplay that characterizes the infection. The presence of RFs drove viral evolution, forcing the virus to develop specific proteins to counteract their activity. The knowledge of the mechanisms that prevent viral infection and their viral counterparts may offer new insights to improve current antiviral strategies. This review provides an overview of the RFs targeting HIV-1 replication and the mechanisms that regulate their expression as well as their impact on viral replication and the clinical course of the disease.

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Retrocopying expands the functional repertoire of APOBEC3 antiviral proteins in primates

10.1101/2020.02.12.944629 ◽

2020 ◽

Author(s):

Lei Yang ◽

Michael Emerman ◽

Harmit S. Malik ◽

Richard N. McLaughlin

Keyword(s):

Rapid Evolution ◽

Endogenous Retroviruses ◽

New World Monkeys ◽

Restriction Factors ◽

New Host ◽

Arms Races ◽

Cytidine Deaminases ◽

Host Restriction ◽

Host Restriction Factors ◽

Evolution Of Viruses

AbstractHost-virus arms races are inherently asymmetric; viruses evolve much more rapidly than host genomes. Thus, there is high interest in discovering mechanisms by which host genomes keep pace with rapidly evolving viruses. One family of restriction factors, the APOBEC3 (A3) cytidine deaminases, has undergone positive selection and expansion via segmental gene duplication and recombination. Here, we show that new copies of A3 genes have also been created in primates by reverse transcriptase-encoding elements like LINE-1 or endogenous retroviruses via a process termed retrocopying. First, we discovered that all simian primate genomes retain the remnants of an ancient A3 retrocopy: A3I. Furthermore, we found that some New World monkeys encode up to ten additional APOBEC3G (A3G) retrocopies. Some of these A3G retrocopies are transcribed in a variety of tissues and able to restrict retroviruses. Our findings suggest that host genomes co-opt retroelement activity in the germline to create new host restriction factors as another means to keep pace with the rapid evolution of viruses. (163)

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Retrocopying expands the functional repertoire of APOBEC3 antiviral proteins in primates

eLife ◽

10.7554/elife.58436 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 4

Author(s):

Lei Yang ◽

Michael Emerman ◽

Harmit S Malik ◽

Richard N McLaughlin

Keyword(s):

Rapid Evolution ◽

Endogenous Retroviruses ◽

New World Monkeys ◽

Restriction Factors ◽

New Host ◽

Arms Races ◽

Cytidine Deaminases ◽

Host Restriction ◽

Host Restriction Factors ◽

Evolution Of Viruses

Host-virus arms races are inherently asymmetric; viruses evolve much more rapidly than host genomes. Thus, there is high interest in discovering mechanisms by which host genomes keep pace with rapidly evolving viruses. One family of restriction factors, the APOBEC3 (A3) cytidine deaminases, has undergone positive selection and expansion via segmental gene duplication and recombination. Here, we show that new copies of A3 genes have also been created in primates by reverse transcriptase-encoding elements like LINE-1 or endogenous retroviruses via a process termed retrocopying. First, we discovered that all simian primate genomes retain the remnants of an ancient A3 retrocopy: A3I. Furthermore, we found that some New World monkeys encode up to ten additional APOBEC3G (A3G) retrocopies. Some of these A3G retrocopies are transcribed in a variety of tissues and able to restrict retroviruses. Our findings suggest that host genomes co-opt retroelement activity in the germline to create new host restriction factors as another means to keep pace with the rapid evolution of viruses. (163)

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Macaque-tropic human immunodeficiency virus type 1: breaking out of the host restriction factors

Frontiers in Microbiology ◽

10.3389/fmicb.2013.00187 ◽

2013 ◽

Vol 4 ◽

Cited By ~ 7

Author(s):

Akatsuki Saito ◽

Hirofumi Akari

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Restriction Factors ◽

Host Restriction ◽

Host Restriction Factors ◽

Immunodeficiency Virus

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Mice Deficient in APOBEC2 and APOBEC3

Molecular and Cellular Biology ◽

10.1128/mcb.25.16.7270-7277.2005 ◽

2005 ◽

Vol 25 (16) ◽

pp. 7270-7277 ◽

Cited By ~ 84

Author(s):

Marie C. Mikl ◽

Ian N. Watt ◽

Mason Lu ◽

Wolf Reik ◽

Sarah L. Davies ◽

...

Keyword(s):

Specific Protein ◽

Restriction Factors ◽

Mouse Development ◽

Host Restriction ◽

Host Restriction Factors ◽

Antibody Diversification ◽

Immunodeficiency Virus ◽

Activation Induced Deaminase ◽

Editing Enzyme ◽

Replication Intermediates

ABSTRACT The activation-induced deaminase/apolipoprotein B-editing catalytic subunit 1 (AID/APOBEC) family comprises four groups of proteins. Both AID, a lymphoid-specific DNA deaminase that triggers antibody diversification, and APOBEC2 (function unknown) are found in all vertebrates examined. In contrast, APOBEC1, an RNA-editing enzyme in gastrointestinal cells, and APOBEC3 are restricted to mammals. The function of most APOBEC3s, of which there are seven in human but one in mouse, is unknown, although several human APOBEC3s act as host restriction factors that deaminate human immunodeficiency virus type 1 replication intermediates. A more primitive function of APOBEC3s in protecting against the transposition of endogenous retroelements has, however, been proposed. Here, we focus on mouse APOBEC2 (a muscle-specific protein for which we find no evidence of a deaminating activity on cytidine whether as a free nucleotide or in DNA) and mouse APOBEC3 (a DNA deaminase which we find widely expressed but most abundant in lymphoid tissue). Gene-targeting experiments reveal that both APOBEC2 (despite being an ancestral member of the family with no obvious redundancy in muscle) and APOBEC3 (despite its proposed role in restricting endogenous retrotransposition) are inessential for mouse development, survival, or fertility.

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HIV-1 Vif versus the APOBEC3 cytidine deaminases: An intracellular duel between pathogen and host restriction factors

Molecular Aspects of Medicine ◽

10.1016/j.mam.2010.06.001 ◽

2010 ◽

Vol 31 (5) ◽

pp. 383-397 ◽

Cited By ~ 46

Author(s):

Silke Wissing ◽

Nicole L.K. Galloway ◽

Warner C. Greene

Keyword(s):

Restriction Factors ◽

Cytidine Deaminases ◽

Host Restriction ◽

Host Restriction Factors ◽

Hiv 1

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Sequence analysis identified an HTLV-1 subtype and mutations of host restriction factors susceptible to HAM/TSP

Journal of the Neurological Sciences ◽

10.1016/j.jns.2017.08.2839 ◽

2017 ◽

Vol 381 ◽

pp. 1006

Author(s):

S. Nozuma ◽

E. Matsuura ◽

T. Matsuzaki ◽

D. Kodama ◽

R. Kubota ◽

...

Keyword(s):

Sequence Analysis ◽

Restriction Factors ◽

Host Restriction ◽

Host Restriction Factors

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Amphotericin b effect on the sensitivity to influenza infection of WI-38 VA-13 cells with IFITM3 gene knockout

Medical academic journal ◽

10.17816/maj76106 ◽

2021 ◽

Vol 21 (3) ◽

pp. 109-112

Author(s):

Kira S. Koryabina ◽

Mariya V. Sergeeva ◽

Andrey B. Komissarov ◽

Nataliya V. Eshchenko ◽

Grigoriy A. Stepanov

Keyword(s):

Amphotericin B ◽

Influenza A Virus ◽

Influenza A ◽

Gene Knockout ◽

Influenza Infection ◽

Restriction Factors ◽

Host Restriction ◽

Host Restriction Factors ◽

Infected Cells ◽

The Difference

BACKGROUND: The application of CRISPR/Cas9 is one of the most rapidly developing areas in biotechnology. This method was used to obtain clones of а human origin cell line with knockout of one or more genes of the IFITM family, representing host restriction factors for influenza infection. Amphotericin B has previously been shown to promote influenza infection by blocking IFITM3 function. AIM: The aim of this study was to evaluate the effect of amphotericin B on the sensitivity of IFITM knockout cells to influenza A virus infection. MATERIALS AND METHODS: WI-38 VA-13 cells and mutant clones with IFITM3 knockout (F3 clone) or IFITM1, IFITM3 knockout (clone E12) were infected with influenza virus A/PR/8/34 (H1N1) in the presence or absence of amphotericin B. Forty-four hours after infection, the culture medium was taken to determine the infectious activity of the virus by titration in the MDCK cell culture, as well as the hemagglutinating activity of the virus. The infected cells were stained with fluorescently labeled antibodies against the viral NP protein, and the number of NP-positive cells was determined by flow cytometry. RESULTS: The addition of amphotericin B increased the hemagglutinating and infectious activity of the virus in WI-38 VA-13cells, while the difference was insignificant for clones with IFITM gene knockout. A similar dependency was obtained for the percent of infected cells. CONCLUSIONS: Mutant cells with a knockout of one or several genes of the IFITM family were equally susceptible to influenza infection regardless of the addition of amphotericin B, which confirms the crucial importance of a defect in the IFITM3 protein in increasing the permissiveness of cells to influenza A virus.

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