Identification of Amino Acid Residues Important for Heparan Sulfate Proteoglycan Interaction within Variable Region 3 of the Feline Immunodeficiency Virus Surface Glycoprotein

Hu, Quan; Fink, Elizabeth; Happer, Meaghan; Elder, John H.

doi:10.1128/jvi.00573-11

Cited by 13 publications

(17 citation statements)

References 63 publications

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“…Although the ORFV CKBP sequence lacks any canonical GAG binding motifs (Cardin and Weintraub, 1989;Hu et al, 2011) (Figure 2C), the positively charged groove in b sheet I is a prominent feature that could interact with negatively charged GAGs (Hu et al, 2011). This role for b sheet I has been described for M-T1 from myxoma virus, which has been shown to bind to GAGs through positively charged residues found on this b sheet (Seet et al, 2001a), and the GAG binding region of EV vCKBP E163 has also been mapped to this location.…”

Section: Resultsmentioning

confidence: 96%

Structures of Orf Virus Chemokine Binding Protein in Complex with Host Chemokines Reveal Clues to Broad Binding Specificity

et al. 2015

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The chemokine binding protein (CKBP) from orf virus (ORFV) binds with high affinity to chemokines from three classes, C, CC, and CXC, making it unique among poxvirus CKBPs described to date. We present its crystal structure alone and in complex with three CC chemokines, CCL2, CCL3, and CCL7. ORFV CKBP possesses a β-sandwich fold that is electrostatically and sterically complementary to its binding partners. Chemokines bind primarily through interactions involving the N-terminal loop and a hydrophobic recess on the ORFV CKBP β-sheet II surface, and largely polar interactions between the chemokine 20s loop and a negatively charged surface groove located at one end of the CKBP β-sheet II surface. ORFV CKBP interacts with leukocyte receptor and glycosaminoglycan binding sites found on the surface of bound chemokines. SEC-MALLS and chromatographic evidence is presented supporting that ORFV CKBP is a dimer in solution over a broad range of protein concentrations.

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Section: Resultsmentioning

confidence: 96%

Structures of Orf Virus Chemokine Binding Protein in Complex with Host Chemokines Reveal Clues to Broad Binding Specificity

et al. 2015

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“…10,11 However, FIV shares with T-cell tropic HIV-1strains the use of the chemokine receptor CXCR4 as the entry receptor for infection. 13 Certain FIV isolates also use heparan sulfate proteoglycans (HSPG), 14,15 and DC-SIGN 16 as binding or attachment receptors to facilitate infection, another characteristic shared with HIV. 17,18 …”

Section: Introductionmentioning

confidence: 99%

“…36,37 Our previous studies revealed that binding of PPRcr (a FIV-PPR isolate adapted to be propagated in CrFK cells) SU to 104-C1 cells (CD134 high ; HSPG low ; CXCR4 low ) was markedly reduced compared to wild type FIV-PPR SU. 15 One potential explanation for the inability of PPRcr SU to bind to CD134 is that mutations involved in CrFK adaptation might alter the conformation of the Env protein and disrupt conformation-dependent binding to CD134.…”

Section: Introductionmentioning

confidence: 99%

Mapping of Receptor Binding Interactions with the FIV Surface Glycoprotein (SU); Implications Regarding Immune Surveillance and Cellular Targets of Infection

Fink²,

Elder³

2012

RRT

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Similar to HIV, FIV uses a two-receptor mechanism to infect CD4+ T cells, the primary target cells in the cat. The T cell activation marker, CD134, serves as a primary binding receptor similar to the role of CD4 for HIV and facilitates interaction with the entry receptor, CXCR4. Heparan sulfate proteoglycans (HSPG) can also act as binding receptors for certain tissue culture adapted FIV and HIV isolates. In the present study, we employed site-directed mutagenesis to investigate the importance of specific residues on the FIV envelope for CD134 and HSPG interactions. We show that certain mutations that disrupt CD134 interactions facilitate HSPG binding by FIV-PPR. In particular, an E407K mutation at the base of the V3 loop knocks out CD134 binding; enhances HSPG binding; and in combination with additional Env mutations E656K and V817I increases entry into CD134−, CXCR4+ target cells by greater than 80-fold over wild type FIV-PPR. The CD134-independent mutant, termed FIV-PPRcr, exhibits a broadened host cell range, but also becomes readily susceptible to CD134-dependent neutralizing monoclonal antibodies. The findings are consistent with the notion that FIV-PPRcr Env has an “open” conformation that readily associates with CXCR4 directly, similar to wild type FIV-PPR Env after CD134 binding. The findings highlight the utility of a two-receptor mechanism that allows FIV V3 residues critical for CXCR4 binding to remain cryptic until reaction occurs with the primary binding receptor, thus thwarting immune surveillance.

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“…One of these mutations (K410N) is in the V3 loop of FIV Env, which has been shown to bind heparan sulfate proteoglycans (HSPGs) and CXCR4 at the surface of CRFK cells to promote membrane attachment and fusion. 66 The other mutation found in Env (T762I) is at the membrane-proximal end of the predicted heptad repeat 2 (HR2) region, which is also involved in CXCR4-mediated membrane fusion. 82,84 Each of these mutations was identified three times in independent isolates, and no isolate contained both.…”

Section: Resultsmentioning

confidence: 99%

“…During the course of this study the CXCR4 and HSPG-binding sites of FIV Env were more clearly indentified by Hu et al, which includes the lysine residue at position 410 of the same molecular clone of FIV Petaluma (34TF10) used in our study. 65,66 We had also speculated that the acquisition of TSG-5’ resistance by mutation of the HR2 domain of FIV Env (T762I) would possibly affect Env-mediated membrane fusion, since the coiled-coil interaction between HR2 and HR1 is critical for fusion. 92 Notably, the HR2 domain of HIV-1 Env is the source of the antiviral peptide enfuvirtide (T20, fuzeon), which functions as a competitive inhibitor of HR1 binding.…”

Section: Discussionmentioning

confidence: 99%

Mutations in the feline immunodeficiency virus envelope glycoprotein confer resistance to a dominant–negative fragment of Tsg101 by enhancing infectivity and cell-to-cell virus transmission

Luttge

Panchal

Puri

et al. 2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The Pro-Ser-Ala-Pro (PSAP) motif in the p2 domain of feline immunodeficiency virus (FIV) Gag is required for efficient virus release, virus replication, and Gag binding to the ubiquitin-E2-variant (UEV) domain of Tsg101. As a result of this direct interaction, expression of an N-terminal fragment of Tsg101 containing the UEV domain (referred to as TSG-5’) inhibits FIV release. In these respects, the FIV p2Gag PSAP motif is analogous to the PTAP motif of HIV-1 p6Gag. To evaluate the feasibility of a late domain-targeted inhibition of virus replication, we created an enriched Crandell-Rees feline kidney (CRFK) cell line (T5’hi) that stably expresses high levels of TSG-5’. Here we show that mutations in either the V3 loop or the second heptad repeat (HR2) domain of the FIV envelope glycoprotein (Env) rescue FIV replication in T5’hi cells without increasing FIV release efficiency. TSG-5’-resistance mutations in Env enhance virion infectivity and the cell-cell spread of FIV when diffusion is limited using a semi-solid growth medium. These findings show that mutations in functional domains of Env confer TSG-5’-resistance, which we propose enhances specific infectivity and the cell-cell transmission of virus to counteract inefficient virus release.

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Identification of Amino Acid Residues Important for Heparan Sulfate Proteoglycan Interaction within Variable Region 3 of the Feline Immunodeficiency Virus Surface Glycoprotein

Cited by 13 publications

References 63 publications

Structures of Orf Virus Chemokine Binding Protein in Complex with Host Chemokines Reveal Clues to Broad Binding Specificity

Structures of Orf Virus Chemokine Binding Protein in Complex with Host Chemokines Reveal Clues to Broad Binding Specificity

Mapping of Receptor Binding Interactions with the FIV Surface Glycoprotein (SU); Implications Regarding Immune Surveillance and Cellular Targets of Infection

Mutations in the feline immunodeficiency virus envelope glycoprotein confer resistance to a dominant–negative fragment of Tsg101 by enhancing infectivity and cell-to-cell virus transmission

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