Accessory Genes Confer a High Replication Rate to Virulent Feline Immunodeficiency Virus

Troyer, Ryan M.; Thompson, Jay; Elder, John H.; VandeWoude, Sue

doi:10.1128/jvi.00752-13

Cited by 16 publications

(16 citation statements)

References 114 publications

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“…Previous studies have shown that feline A3 cytidine deaminases can act as restriction factors for FIV, which are counteracted by the FIV Vif protein (3,43,45,47). However, the molecular interaction between FIV Vif and feline A3s is poorly understood.…”

Section: Resultsmentioning

confidence: 99%

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Feline Immunodeficiency Virus Vif N-Terminal Residues Selectively Counteract Feline APOBEC3s

Zhang

Cano-Ortiz

et al. 2016

J Virol

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Section: Resultsmentioning

confidence: 99%

“…Similar to human A3-mediated restriction of HIV-1⌬vif, feline A3s are shown to inhibit FIV⌬vif (3,(43)(44)(45)(46)(47). Moreover, natural polymorphisms of feline APOBEC3s correlate with FIV and FeLV infection in domestic cats (48).…”

mentioning

confidence: 99%

Feline Immunodeficiency Virus Vif N-Terminal Residues Selectively Counteract Feline APOBEC3s

Zhang

Cano-Ortiz

et al. 2016

J Virol

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“…Further, we observed similar delays in spreading replication in CrFKs compared to peripheral blood mononuclear cells (PBMCs) derived from domestic cats and co-cultured with CrFK cells infected with Δvif FIV (69). CrFK cells express all fA3 proteins; hence, the delay in spreading WT replication may have been due to the antiviral activity of fA3 proteins in the absence of Vif (70). In support of this, all Vif mutant viruses were replication-incompetent, and the block in replication was sustained over 18 and 40 days at two different MOI (Fig 4 C and 4 D ).…”

Section: Discussionmentioning

confidence: 99%

“…hA3s and HIV-1 Vif require different binding motifs to interact with fA3s and FIV Vif (71). Further, Troy and colleagues showed that the pathogenicity of FIV depends on the Vif isolate (70), which might correlate with the interaction, or lack thereof, between FIV C36 Vif and fCul5. Thus, our results demonstrate that a single residue within the BC box, TLQ/TAQ or A205L, of FIV Vif can induce fA3Z3 and fA3Z2bZ3 degradation, and that the KCCC motif does not mediate the interaction between fCul5 and FIV Vif.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Vif domains that mediate Feline Immunodeficiency Virus antagonism of APOBEC3-H and APOBEC3-CH restriction

Sims

Maynard

Poeschla

2017

Preprint

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Feline immunodeficiency virus (FIV) Vif mediates degradation of two anti-lentiviral feline APOBEC3 (fA3) proteins, fA3Z3 and fA3Z2bZ3. HIV-1 Vif targets the restriction factor human APOBEC3G (A3G, hA3Z2g-Z1c) for proteasome degradation to mediate viral evasion. Despite this similarity, FIV and HIV-1 Vif share limited homology. Vif binds hA3Z2g-Z1c through its N-terminal region, while its C-terminal region binds to an E3-ligase complex containing Cullin5 and Elongin B/C. Further, HIV-1 Vif contains critical domains in its C-terminus, including an adjacent BC box, the only shared domain between FIV and HIV-1 Vif, and a non-classical zinc finger (HCCH) domain. Felid lentivirus Vif, however, contains a highly conserved KCCC motif. While both Vifs have evolved to counteract select A3 antiretroviral proteins, the FIV Vif domains necessary to target fA3s for degradation are incompletely understood. To identify these domains, we used the well-characterized HIV-1 Vif domains to show that distinct mutations within the BC box of FIV Vif prevent fA3Z3 and fA3Z2bZ3 degradation and reduce virion infectivity. We also found that mutating any single residue in the KCCC motif blocked fA3 targeting and impaired FIV infectivity and replication. These mutations also failed to disrupt the FIV Vif and Cullin5 interaction. Further, we showed that, in contrast to the HCCH domain in HIV-1 Vif, the KCCC domain of FIV Vif does not bind zinc. However, unlike HIV-1 Vif, FIV Vif (C36 isolate) reduces intracellular levels of co-expressed Cullin5 proteins, a novel finding. Our results reveal important C-terminal residues in FIV Vif and show that the BC box and KCCC regions are critical for fA3 degradation, infectivity, and spreading replication.

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“…To confirm the presence of infectious FIV particles in saliva of infected cats, duplicate cell cultures consisting of GFox cells (CrFK cells overexpressing CD134) were established in 96-well plates at 20,000 cells/well and allowed to attach at 37°C overnight [ 53 , 56 ]. GFox cell cultures were maintained at 37°C and 5% CO 2 , in 240 μl of culture medium composed of Dulbecco's modified Eagle's medium (DMEM) with GlutaMAX-1, 10% fetal bovine serum (FBS), and 1x penicillin-streptomycin (10,000 U/liter penicillin and 10,000 μg/liter streptomycin), as well as 1 μg/ml of Fungizone ® (Amphotericin B; Life Technologies) [ 57 ]. At day 0, 10 μl of saliva from 5 FIV-infected and 1 sham-inoculated (uninfected) cats (collected as previously described) were added to the previously established Gfox cell culture, bringing the total volume to 250 μl (1:25 dilution of saliva).…”

Section: Methodsmentioning

confidence: 99%

Pathogenesis of oral FIV infection

et al. 2017

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Feline immunodeficiency virus (FIV) is the feline analogue of human immunodeficiency virus (HIV) and features many hallmarks of HIV infection and pathogenesis, including the development of concurrent oral lesions. While HIV is typically transmitted via parenteral transmucosal contact, recent studies prove that oral transmission can occur, and that saliva from infected individuals contains significant amounts of HIV RNA and DNA. While it is accepted that FIV is primarily transmitted by biting, few studies have evaluated FIV oral infection kinetics and transmission mechanisms over the last 20 years. Modern quantitative analyses applied to natural FIV oral infection could significantly further our understanding of lentiviral oral disease and transmission. We therefore characterized FIV salivary viral kinetics and antibody secretions to more fully document oral viral pathogenesis. Our results demonstrate that: (i) saliva of FIV-infected cats contains infectious virus particles, FIV viral RNA at levels equivalent to circulation, and lower but significant amounts of FIV proviral DNA; (ii) the ratio of FIV RNA to DNA is significantly higher in saliva than in circulation; (iii) FIV viral load in oral lymphoid tissues (tonsil, lymph nodes) is significantly higher than mucosal tissues (buccal mucosa, salivary gland, tongue); (iv) salivary IgG antibodies increase significantly over time in FIV-infected cats, while salivary IgA levels remain static; and, (v) saliva from naïve Specific Pathogen Free cats inhibits FIV growth in vitro. Collectively, these results suggest that oral lymphoid tissues serve as a site for enhanced FIV replication, resulting in accumulation of FIV particles and FIV-infected cells in saliva. Failure to induce a virus-specific oral mucosal antibody response, and/or viral capability to overcome inhibitory components in saliva may perpetuate chronic oral cavity infection. Based upon these findings, we propose a model of oral FIV pathogenesis and suggest alternative diagnostic modalities and translational approaches to study oral HIV infection.

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Accessory Genes Confer a High Replication Rate to Virulent Feline Immunodeficiency Virus

Cited by 16 publications

References 114 publications

Feline Immunodeficiency Virus Vif N-Terminal Residues Selectively Counteract Feline APOBEC3s

Feline Immunodeficiency Virus Vif N-Terminal Residues Selectively Counteract Feline APOBEC3s

Characterization of Vif domains that mediate Feline Immunodeficiency Virus antagonism of APOBEC3-H and APOBEC3-CH restriction

Pathogenesis of oral FIV infection

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