Evolution of Two Amino Acid Positions Governing Broad Neutralization Resistance in a Strain of Feline Immunodeficiency Virus over 7 Years of Persistence in Cats

Abstract

Fresh isolates of lentiviruses are characterized by an outstanding resistance to antibody-mediated neutralization. By investigating the changes that occurred in a neutralization-sensitive tissue culture-adapted strain of feline immunodeficiency virus after it was reinoculated into cats, a previous study had identified two amino acid positions of the surface glycoprotein (residues 481 and 557) which govern broad neutralization resistance (BNR) in this virus. By extending the follow-up of six independently evolving in vivo variants of such virus for up to 92 months, we now show that the changes at the two BNR-governing positions not only were remarkably stereotyped but also became fixed in an ordered sequential fashion with the duration of in vivo infection. In one variant, the two positions were also seen to slowly alternate at determining BNR. Evidence that evolution at the BNR-governing positions was accompanied, and possibly driven, by changes in the antigenic makeup of the viral surface brought about by the mutations at such positions is also presented.

Neutralization of feline immunodeficiency virus by antibodies targeting the V5 loop of Env

“…V5 was mapped by using synthetic peptides for a possible linear epitope based on the sequence of the 19k1-560 strain (Siebelink et al, 1995), and it was demonstrated that a single mutation at position 560 may be involved concurrently with another mutation at 483 (V4 loop) in one or more conformational epitopes, but no linear epitope was mapped in V5. Further, two independent mutations have been reported that resulted in the creation of potential N-linked glycosylation sites in V4 (K481N) and V5 (S557N) and which contributed to the conversion from a neutralization-sensitive to a neutralization-resistant phenotype (Giannecchini et al, 2001;Pistello et al, 2003). In comparison, the conversion from a weakly neutralized or neutralization-resistant to a strongly neutralized phenotype described herein was mediated by mutation of V5 alone.…”

“…Previous studies have demonstrated the importance of V5 in virus neutralization (Giannecchini et al, 2001;Pistello et al, 2003;Siebelink et al, 1995). V5 was mapped by using synthetic peptides for a possible linear epitope based on the sequence of the 19k1-560 strain (Siebelink et al, 1995), and it was demonstrated that a single mutation at position 560 may be involved concurrently with another mutation at 483 (V4 loop) in one or more conformational epitopes, but no linear epitope was mapped in V5.…”

“…By the time functional NAbs develop, virus variants that can escape the monospecific serum may have already evolved in vivo. The solution to this dilemma would appear to lie in the identification of framework determinants in Env that induce antibodies that are broadly active, refocusing the immune response either by silencing the immunodominant (but ultimately ineffectual) determinants in V4 and V5, or by presenting them in a such a way as to induce antibodies that recognize structures or motifs that are difficult or impossible for the virus to vary.Previous studies have demonstrated the importance of V5 in virus neutralization (Giannecchini et al, 2001;Pistello et al, 2003;Siebelink et al, 1995). V5 was mapped by using synthetic peptides for a possible linear epitope based on the sequence of the 19k1-560 strain (Siebelink et al, 1995), and it was demonstrated that a single mutation at position 560 may be involved concurrently with another mutation at 483 (V4 loop) in one or more conformational epitopes, but no linear epitope was mapped in V5.…”

Feline Immunodeficiency Virus (FIV) Neutralization: A Review

“…A single mutation at position 560 in V5 may be involved concurrently with an additional mutation at 483 in the V4 loop to form a conformation-dependent determinant for neutralizing antibody [ 68 ]. Independently, two mutations that resulted in the creation of potential sites for N-linked glycosylation in V4 (K481N) and V5 (S557N) contributed to the conversion of FIV from a neutralization-sensitive to neutralization-resistant phenotype [ 65 , 69 ]. Further evidence for the importance of the V5 region of FIV to the control of viral replication in vivo has been uncovered in analyses of the evolution of a molecular clone of the GL8 strain over time.…”

FIV as a Model for HIV: An Overview

“…457 Although the V3 immunodominant domain is the only FIV Env determinant consistently shown to induce antibodies capable of neutralizing virus in vitro, [252][253][254] determinants within domains V4 and V5, including residues 481 and 551, were also shown to confer broad neutralization resistance (BNR) in primary isolates passaged in vivo (Figure 3). 455,[458][459][460][461][462] The remaining FIV envelope linear epitopes mapped by binding assays are most likely inaccessible for neutralization due to the complex oligomeric structure and extensive glycosylation of native FIV SU, a property shared with HIV-1 SU. 449,454,463 Expression of both neutralizing epitopes and tropism determinants by the FIV hypervariable V3 domain is an important function also described for the V3 domain of HIV-1 surface glycoprotein.…”