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Comparative Study
. 2006 Sep;80(17):8745-62.
doi: 10.1128/JVI.00956-06.

Antibody responses elicited in macaques immunized with human immunodeficiency virus type 1 (HIV-1) SF162-derived gp140 envelope immunogens: comparison with those elicited during homologous simian/human immunodeficiency virus SHIVSF162P4 and heterologous HIV-1 infection

Nina R Derby  1 , Zane Kraft, Elaine Kan, Emma T Crooks, Susan W Barnett, Indresh K Srivastava, James M Binley, Leonidas Stamatatos
Affiliations
Comparative Study

Antibody responses elicited in macaques immunized with human immunodeficiency virus type 1 (HIV-1) SF162-derived gp140 envelope immunogens: comparison with those elicited during homologous simian/human immunodeficiency virus SHIVSF162P4 and heterologous HIV-1 infection

Nina R Derby et al. J Virol. 2006 Sep.

Erratum in

  • J Virol. 2007 Feb;81(3):1538

Abstract

The antibody responses elicited in rhesus macaques immunized with soluble human immunodeficiency virus (HIV) Env gp140 proteins derived from the R5-tropic HIV-1 SF162 virus were analyzed and compared to the broadly reactive neutralizing antibody responses elicited during chronic infection of a macaque with a simian/human immunodeficiency virus (SHIV) expressing the HIV-1 SF162 Env, SHIV(SF162P4), and humans infected with heterologous HIV-1 isolates. Four gp140 immunogens were evaluated: SF162gp140, DeltaV2gp140 (lacking the crown of the V2 loop), DeltaV3gp140 (lacking the crown of the V3 loop), and DeltaV2DeltaV3gp140 (lacking both the V2 and V3 loop crowns). SF162gp140 and DeltaV2gp140 have been previously evaluated by our group in a pilot study, but here, a more comprehensive analysis of their immunogenic properties was performed. All four gp140 immunogens elicited stronger anti-gp120 than anti-gp41 antibodies and potent homologous neutralizing antibodies (NAbs) that primarily targeted the first hypervariable region (V1 loop) of gp120, although SF162gp140 also elicited anti-V3 NAbs. Heterologous NAbs were elicited by SF162gp140 and DeltaV2gp140 but were weak in potency and narrow in specificity. No heterologous NAbs were elicited by DeltaV3gp140 or DeltaV2DeltaV3gp140. In contrast, the SHIV(SF162P4)-infected macaque and HIV-infected humans generated similar titers of anti-gp120 and anti-gp41 antibodies and NAbs of significant breadth against primary HIV-1 isolates, which did not target the V1 loop. The difference in V1 loop immunogenicity between soluble gp140 and virion-associated gp160 Env proteins derived from SF162 may be the basis for the observed difference in the breadth of neutralization in sera from the immunized and infected animals studied here.

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Figures

FIG. 1.
FIG. 1.
Recognition of gp140s by MAbs. The binding of MAbs directed to linear and conformational gp120 and gp41 epitopes on SF162gp140F (filled squares), ΔV2gp140F (open diamonds), ΔV3gp140F (filled circles), and ΔV2ΔV3gp140F (open squares) was determined as discussed in Materials and Methods.
FIG. 2.
FIG. 2.
Recognition of gp140s by serum antibodies. Sera collected 4 weeks following the recombinant gp140 immunization step from the immunized animals, from the SHIVSF162P4-infected macaque, C640, at day 643 postinfection and HIVIG were added to ELISA wells coated with the indicated gp140s, and the binding of serum IgG was determined. Sera from each immunized group were pooled. Preimmunization or preinfection sera were used as a control for nonspecific binding, and the means with standard deviation of results from three separate experiments are shown.
FIG. 3.
FIG. 3.
Neutralization of SF162 by immune sera and HIVIG. Pooled sera collected from gp140-imunized animals 4 weeks after protein boost or from mock-immunized animals, sera collected from the SHIVSF162P4-infected macaque, C640, at days 178, 304, and 643 postinfection, and HIVIG were tested for neutralization against SF162. The percent neutralization was calculated using preimmunization or preinfection sera as described in Materials and Methods. The lowest serum dilution tested was 1:20. The highest HIVIG concentration was 0.5 mg/ml, which is roughly equivalent to a 1:20 serum dilution.
FIG. 4.
FIG. 4.
Mapping the epitopes of anti-SF162 neutralizing antibodies. (A) Peptide-mediated interference of SF162 neutralization by sera from the ΔV2ΔV3gp140-immunized macaque CN63. Neutralization was performed in the absence (filled symbols and solid lines) and presence (open symbols and dashed lines) of V1 (squares) or V3 (circles) peptides. The percent reduction in neutralization at the IC70 is indicated. (B) Peptide-mediated interference of SF162 neutralization by sera from the SHIVSF162P4-infected macaque C640. The symbols are the same as in panel A. (C) Neutralization of SF162 and Δ2F5.4E10 by MAbs. IgG1b12, squares; 2F5, circles; 4E10, triangles; SF162, filled symbols; and Δ2F5.4E10, open symbols. (D) Neutralization of SF162 and Δ2F5.4E10 by pooled sera from the immunized animals and from the SHIVSF162P4-infected animal. The IC70 is shown for each serum pool on SF162 (black bars), and neutralization at the IC70 for SF162 is shown for each serum pool on Δ2F5.4E10 (white bars).
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