Abstract:The replication of lentiviruses highly depends on host cellular factors, which defines their species-specific tropism. Cellular restriction factors that can inhibit lentiviral replication were recently identified. Feline immunodeficiency virus (FIV) was found to be sensitive to several feline cellular restriction factors, such as apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3 (APOBEC3) and tetherin, but FIV evolved to counteract them. Here, we describe the molecular mechanisms by which feli… Show more
“…The involvement of host cellular factors is required for the Vif-induced degradation of A3 proteins, and the cellular factors recruited by different lentiviral Vif proteins are virus-specific ( Zhang et al, 2018 ). For instance, HIV-1 Vif hijacks CUL5, ELOB/C and CBF-β to neutralize the antiviral activity of human A3 proteins ( Jager et al, 2011 ; Zhang et al, 2011 ), while Cullin 2 (CUL2), ELOB/C, and RBX1, but not CUL5 or CBF-β, were employed by BIV and JDV Vif to form a CRL2 E3 ubiquitin ligase to degrade the restrictive bovine A3 proteins ( Zhang W. et al, 2014 ; Su et al, 2018 ).…”
Caprine arthritis encephalitis virus (CAEV) is a lentivirus that causes multisystemic chronic disorders in sheep and goats. It encodes Vif to counteract the restriction of Ovis aries A3Z2-Z3 (oaA3Z2-Z3) by inducing their degradation. Nevertheless, the mechanisms underlying the interplay between CAEV Vif and OaA3Z2-Z3 have yet to be elucidated. Here, we identified the cellular factors ElonginB/C, CYPA and Cullin5 as being hijacked by CAEV Vif as well as several functional domains of CAEV Vif required for degrading oaA3Z2-Z3. Moreover, we determined that CAEV Vif assembled E3 ubiquitin ligase stepwise via its SLE motif (170SLE172) to recruit ElonginB/C, the P21 site and the zinc finger motif (C132-C134-C154-C157) to recruit CYPA, as well as the hydrophobic domain (141IR142) to recruit Cullin5. And this CAEV Vif-mediated E3 ligase triggers the proteasomal degradation of oaA3Z2-Z3, which directly bind CAEV Vif through residues Y39 and L44. In particular, CYPA played an essential role in the process to regulate ligase assembly, which was analogous to CBF-β, the essential regulator for HIV-1 and SIV-mediated E3 ligase, indicating that there is a modular conservation and lineage-specific preference for cellular partners required by Vifs from different subgroups of lentiviruses. Taken together, these findings provide important insights regarding the CAEV Vif function and deepen our understanding of the arms race between the lentiviruses and their hosts.
“…The involvement of host cellular factors is required for the Vif-induced degradation of A3 proteins, and the cellular factors recruited by different lentiviral Vif proteins are virus-specific ( Zhang et al, 2018 ). For instance, HIV-1 Vif hijacks CUL5, ELOB/C and CBF-β to neutralize the antiviral activity of human A3 proteins ( Jager et al, 2011 ; Zhang et al, 2011 ), while Cullin 2 (CUL2), ELOB/C, and RBX1, but not CUL5 or CBF-β, were employed by BIV and JDV Vif to form a CRL2 E3 ubiquitin ligase to degrade the restrictive bovine A3 proteins ( Zhang W. et al, 2014 ; Su et al, 2018 ).…”
Caprine arthritis encephalitis virus (CAEV) is a lentivirus that causes multisystemic chronic disorders in sheep and goats. It encodes Vif to counteract the restriction of Ovis aries A3Z2-Z3 (oaA3Z2-Z3) by inducing their degradation. Nevertheless, the mechanisms underlying the interplay between CAEV Vif and OaA3Z2-Z3 have yet to be elucidated. Here, we identified the cellular factors ElonginB/C, CYPA and Cullin5 as being hijacked by CAEV Vif as well as several functional domains of CAEV Vif required for degrading oaA3Z2-Z3. Moreover, we determined that CAEV Vif assembled E3 ubiquitin ligase stepwise via its SLE motif (170SLE172) to recruit ElonginB/C, the P21 site and the zinc finger motif (C132-C134-C154-C157) to recruit CYPA, as well as the hydrophobic domain (141IR142) to recruit Cullin5. And this CAEV Vif-mediated E3 ligase triggers the proteasomal degradation of oaA3Z2-Z3, which directly bind CAEV Vif through residues Y39 and L44. In particular, CYPA played an essential role in the process to regulate ligase assembly, which was analogous to CBF-β, the essential regulator for HIV-1 and SIV-mediated E3 ligase, indicating that there is a modular conservation and lineage-specific preference for cellular partners required by Vifs from different subgroups of lentiviruses. Taken together, these findings provide important insights regarding the CAEV Vif function and deepen our understanding of the arms race between the lentiviruses and their hosts.
“…Mapping and identification of A3 genes takes advantage the presence of genes CBX6 and CBX7 upstream and downstream of the gene locus, respectively. For the purpose of this article, particular attention will be played to species known to be hosts for coronaviruses – bats and humans – but we draw attention to an extensive review of the activity and characteristics of feline A3s ( Zhang et al, 2018 ). Fig.…”
Section: Diversity Of Function In Humansmentioning
“…This finding may also be relevant to FeLV as A3Z2-Z3 has been shown to significantly reduce FeLV in vitro infectivity while A3Z3 had only marginal impact on FeLV in vitro infectivity [35]. It is possible A3Z2-Z3 transcripts could be produced predominantly by a specific cell type not identified in the current study or A3Z2-Z3 protein quantity may be higher than what would be expected based on the very low level of mRNA as suggested by Zhang et al [48]. Future studies comparing A3 protein levels in cells and tissues will be useful to verify expression based on mRNA levels.…”
Section: Discussionmentioning
confidence: 50%
“…For instance, interactions between Vif of simian immunodeficiency virus (SIV) and human A3 haplotypes significantly influenced the outcome of spillover infections that marked the inception of the HIV-1 pandemic [16,43]. Despite such implications, the evolutionary pathways of lentiviral adaptation to A3 repertoires of target and non-target hosts are only partially understood [48]. Several studies have documented restriction of HIV-1 by feline A3s, with A3Z2-Z3 conferring the greatest antiviral activity [35,47,49,50].…”
Feline immunodeficiency virus (FIV) is a naturally occurring T-cell tropic lentiviral disease of felids with many similarities to HIV/AIDS in humans. Similar to primate lentiviral-host interactions, feline APOBEC3 (A3) has been shown to inhibit FIV infection in a host-specific manner and feline A3 degradation is mediated by FIV Vif. Further, infection of felids with non-native FIV strains results in restricted viral replication in both experimental and naturally occurring infections. However, the link between molecular A3-Vif interactions and A3 biological activity during FIV infection has not been well characterized. We thus examined expression of the feline A3 genes A3Z2, A3Z3 and A3Z2-Z3 during experimental infection of domestic cats with host-adapted domestic cat FIV (referred to as FIV) and non-adapted Puma concolor FIV (referred to as puma lentivirus, PLV). We determined A3 expression in different tissues and blood cells from uninfected, FIV-infected, PLV-infected and FIV/PLV co-infected cats; and in purified blood cell subpopulations from FIV-infected and uninfected cats. Additionally, we evaluated regulation of A3 expression by cytokines, mitogens, and FIV infection in cultured cells. In all feline cells and tissues studied, there was a striking difference in expression between the A3 genes which encode FIV inhibitors, with A3Z3 mRNA abundance exceeding that of A3Z2-Z3 by 300-fold or more. Interferon-alpha treatment of cat T cells resulted in upregulation of A3 expression, while treatment with interferon-gamma enhanced expression in cat cell lines. In cats, secondary lymphoid organs and peripheral blood mononuclear cells (PBMC) had the highest basal A3 expression levels and A3 genes were differentially expressed among blood T cells, B cells, and monocytes. Acute FIV and PLV infection of cats, and FIV infection of primary PBMC resulted in no detectable change in A3 expression with the exception of significantly elevated A3 expression in the thymus, the site of highest FIV replication. We conclude that cat A3 expression is regulated by cytokine treatment but, by and large, lentiviral infection did not appear to alter expression. Differences in A3 expression in different blood cell subsets did not appear to impact FIV viral replication kinetics within these cells. Furthermore, the relative abundance of A3Z3 mRNA compared to A3Z2-Z3 suggests that A3Z3 may be the major active anti-lentiviral APOBEC3 gene product in domestic cats.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
