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. 2003 Feb;77(4):2310-20.
doi: 10.1128/jvi.77.4.2310-2320.2003.

Changes in the immunogenic properties of soluble gp140 human immunodeficiency virus envelope constructs upon partial deletion of the second hypervariable region

Indresh K Srivastava  1 , Keating VanDorsten, Lucia Vojtech, Susan W Barnett, Leonidas Stamatatos
Affiliations

Changes in the immunogenic properties of soluble gp140 human immunodeficiency virus envelope constructs upon partial deletion of the second hypervariable region

Indresh K Srivastava et al. J Virol. 2003 Feb.

Abstract

Immunization of macaques with the soluble oligomeric gp140 form of the SF162 envelope (SF162gp140) or with an SF162gp140-derived construct lacking the central region of the V2 loop (DeltaV2gp140) results in the generation of high titers of antibodies capable of neutralizing the homologous human immunodeficiency virus type 1 (HIV-1), SF162 virus (Barnett et al. J. Virol. 75:5526-5540, 2001). However, the DeltaV2gp140 immunogen is more effective than the SF162gp140 immunogen in eliciting the generation of antibodies capable of neutralizing heterologous HIV-1 isolates. This indicates that deletion of the V2 loop alters the immunogenicity of the SF162gp140 protein. The present studies were aimed at identifying the envelope regions whose immunogenicity is altered following V2 loop deletion. We report that the antibodies elicited by the SF162gp140 immunogen recognize elements of the V1, V2, and V3 loops, the CD4-binding site, and the C1 and C2 regions on the homologous SF162 gp120. With the exception of the V1 and V2 loops, the same regions are recognized on heterologous gp120 proteins. Surprisingly, although a minority of the SF162gp140-elicited antibodies target the V3 loop on the homologous gp120, the majority of the antibodies elicited by this immunogen that are capable of binding to the heterologous gp120s tested recognize their V3 loops. Deletion of the V2 loop has two effects. First, it alters the immunogenicity of the V3 and V1 loops, and second, it renders the C5 region immunogenic. Although deletion of the V2 loop does not result in an increase in the immunogenicity of the CD4-binding site per se, the relative ratio of anti-CD4-binding site to anti-V3 loop antibodies that bind to the heterologous gp120s tested is higher in sera collected from the DeltaV2gp140-immunized animals than in the SF162gp140-immunized animals. Overall, our studies indicate that it is possible to alter the immunogenic structure of the HIV envelope by introducing specific modifications.

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Figures

FIG. 1.
FIG. 1.
Development of antibodies (end-point ELISA titers) in animals immunized with the SF162gp140C (animals P655 [□] and N472 [○]) immunogen, the ΔV2gp140C immunogen (animals H445 • and J408 ▪), and the ΔV2gp140F immunogen (animals K863 [⧫] and I708 [▾]) that are capable of binding to the oligomeric gp140 envelope. Sera from the SF162gp140-immunized animals were evaluated against the SF162gp140 protein, whereas those from the ΔV2gp140-immunized animals were evaluated against the ΔV2gp140 protein. Black arrows indicate the time of DNA immunization, and white arrows indicate the time of protein immunization.
FIG. 2.
FIG. 2.
Titration of serum antibodies against the homologous SF162 and heterologous SF2 and US4 gp120 proteins. Sera were collected following the protein administration from animals P655 and N472 (immunized with the SF162gp140C immunogen), animals H445 and J408 (immunized with the ΔV2gp140C immunogen), and animals I708 and K863 (immunized with the ΔV2gp140F immunogen). ∗, nonspecific binding recorded with sera collected prior to the initiation of immunization (pre-bleeds); •, binding of postimmunization sera to the SF162 gp120 protein; □, binding of postimmunization sera to the SF2 gp120 protein; ◊, binding of postimmunization sera to the US4 gp120 protein.
FIG. 3.
FIG. 3.
Neutralization of the homologous SF162 and heterologous SF2 viruses. The neutralizing potential of sera collected from the SF162gp140C-immunized (animals N472 [◊] and P655 [□]), ΔV2gp140C-immunized (animals H445 [▪] and J408 [▴]), and ΔV2gp140F-immunized (animals I708 [•] and K863 [⧫]) macaques against the SF162 and SF2 HIV-1 isolates was evaluated by determining the percent inhibition of PBMC infection at various dilutions. Results have been corrected for nonspecific inhibition of infection (i.e., in the presence of sera collected prior to the initiation of immunization). Results are the averages of three to six independent experiments.
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