Modulation of the virus-receptor interaction by mutations in the V5 loop of feline immunodeficiency virus (FIV) following in vivoescape from neutralising antibody

Abstract

BackgroundIn the acute phase of infection with feline immunodeficiency virus (FIV), the virus targets activated CD4+ T cells by utilising CD134 (OX40) as a primary attachment receptor and CXCR4 as a co-receptor. The nature of the virus-receptor interaction varies between isolates; strains such as GL8 and CPGammer recognise a "complex" determinant on CD134 formed by cysteine-rich domains (CRDs) 1 and 2 of the molecule while strains such as PPR and B2542 require a more "simple" determinant comprising CRD1 only for infection. These differences in receptor recognition manifest as variations in sensitivity to receptor antagonists. In this study, we ask whether the nature of the virus-receptor interaction evolves in vivo.ResultsFollowing infection with a homogeneous viral population derived from a pathogenic molecular clone, a quasispecies emerged comprising variants with distinct sensitivities to neutralising antibody and displaying evidence of conversion from a "complex" to a "simple" interaction with CD134. Escape from neutralising antibody was mediated primarily by length and sequence polymorphisms in the V5 region of Env, and these alterations in V5 modulated the virus-receptor interaction as indicated by altered sensitivities to antagonism by both anti-CD134 antibody and soluble CD134.ConclusionsThe FIV-receptor interaction evolves under the selective pressure of the host humoral immune response, and the V5 loop contributes to the virus-receptor interaction. Our data are consistent with a model whereby viruses with distinct biological properties are present in early versus late infection and with a shift from a "complex" to a "simple" interaction with CD134 with time post-infection.

Feline Tetherin Efficiently Restricts Release of Feline Immunodeficiency Virus but Not Spreading of Infection

“…Combined with our own observations in which CD134-independent strains of FIV arose in vivo following infection with the CD134-dependent GL8 strain of FIV (23), it would appear that there is selective pressure in vivo for the generation of CD134-independent strains of virus. We have shown previously that the humoral immune response can exert a selective pressure that is capable of modulating the virus-receptor interaction (64). The activities of feline tetherin that we have observed in vitro may exhert an additional selective pressure on receptor use in vivo.…”

The virus–receptor interaction in the replication of feline immunodeficiency virus (FIV)

“…Given the role of N-linked glycosylation in shielding Env from the humoral immune response, the humoral response to infection may offer a driving force for the switch from CRD2-dependent to CRD2-independent infection. Consistent with this hypothesis, viral variants that emerged in vivo following infection with a clonal preparation of GL8, and which resisted neutralisation by homologous serum, displayed a shift in receptor usage from CRD2-dependent to CRD-2 independent [23 • ]. For one variant, exchange of the hypervariable V5 loop of Env alone was sufficient to render the virus both neutralising antibody resistant and CRD2-independent [23 • ].…”

Domestic cat microsphere immunoassays: Detection of antibodies during feline immunodeficiency virus infection

“…The function of these virus-specific antibodies can vary in terms of disease outcome. For example, antibodies to specific FIV SU epitopes, such as the V4 and V5 regions, are capable of neutralizing the virus (Siebelink et al, 1993; Siebelink et al, 1996; Samman et al, 2010; Willett et al, 2010) and, as observed with HIV patients, the presence of α-Gag/CA antibodies correlates with delayed disease progression (Lange et al, 1986; Weber et al, 1987; Cheingsong-Popov et al, 1991; Chargelegue et al, 1995; Binley et al, 1997). The level and kinetics of the FIV-specific antibody response varies depending on inoculation route and/or viral strain, as well as among individual cats (Rimmelzwaan et al, 1994; Calzolari et al, 1995; Burkhard et al, 2001; Grant et al, 2009).…”