Vaccine-elicited V3 loop-specific antibodies in rhesus monkeys and control of a simian-human immunodeficiency virus expressing a primary patient human immunodeficiency virus type 1 isolate envelope

Abstract

Vaccine-elicited antibodies specific for the third hypervariable domain of the surface gp120 of human immunodeficiency virus type 1 (HIV-1) (V3 loop) were assessed for their contribution to protection against infection in the simian-human immunodeficiency virus (SHIV)/rhesus monkey model. Peptide vaccine-elicited anti-V3 loop antibody responses were examined for their ability to contain replication of SHIV-89.6, a nonpathogenic SHIV expressing a primary patient isolate HIV-1 envelope, as well as SHIV-89.6P, a pathogenic variant of that virus. Low-titer neutralizing antibodies to SHIV-89.6 that provided partial protection against viremia following SHIV-89.6 infection were generated. A similarly low-titer neutralizing antibody response to SHIV-89.6P that did not contain viremia after infection with SHIV-89.6P was generated, but a trend toward protection against CD4+ T-lymphocyte loss was seen in these infected monkeys. These observations suggest that the V3 loop on some primary patient HIV-1 isolates may be a partially effective target for neutralizing antibodies induced by peptide immunogens.

FIG. 1

Location and sequence of the C4/89.6-V3 and C4/89.6P-V3 peptides. Peptides 39 amino acids in length contained sequences from the crown and N-terminal portion of the V3 loop synthesized C-terminal to a 16-amino-acid stretch of the C4 helper determinant of gp120. The 89.6 and 89.6P peptides differed by a single arginine (R)-to-glutamic acid (E) substitution in V3 as shown.

FIG. 2

Neutralizing antibody response in peptide-immunized animals before and after challenge with SHIV-89.6. Animals were inoculated with either C4/scbl-V3 (A) or C4/89.6-V3 (B) at weeks 0, 4, 12, 24, 89, 95, 101, and 111 and were challenged with SHIV-89.6 at week 113. Neutralizing antibodies to SHIV-89.6 were measured in MT-2 cells at multiple times before and after challenge. Peptide inoculations were made at the times indicated (∧). Arrow, day of challenge. The lowest serum dilution tested was 1:20 (negative results were given a value of 20 for presentation).

FIG. 3

Neutralizing antibody response in peptide-immunized animals before and after challenge with either SHIV-89.6P or SHIV-89.6. Animals were inoculated with either C4/scbl-V3 or C4/89.6P-V3 at weeks 0, 6, 12, 18, 24, and 31 and were challenged with either SHIV-89.6P or SHIV-89.6 at week 33. Neutralizing antibodies to SHIV-89.6 (A) and SHIV-89.6P (B) were measured in MT-2 cells at multiple times throughout the immunization schedule and postchallenge. Peptide inoculations were made at the times indicated (∧). Arrow, day of challenge. The lowest serum dilution tested was 1:20 for SHIV-89.6 and 1:5 for SHIV-89.6P (negative results were given values of 20 and 5, respectively, for presentation).

FIG. 4

Neutralizing antibody specificity generated by C4/89.6-V3 peptide immunization. Serum samples were obtained 2 weeks after final boosting with the C4/89.6-V3 peptide. Each serum sample was incubated for 1 h at 37°C with either no peptide (solid circles), C4/scbl-V3 peptide (open circles), or C4/89.6-V3 peptide (solid inverted triangles) and then assessed for neutralizing activity against SHIV-89.6 in MT-2 cells.

FIG. 5

Sequential plasma viral load measurements in rhesus monkeys immunized with a control peptide (C4/scbl-V3), an experimental homologous peptide (C4/89.6-V3), or a control heterologous peptide (C4/89.6P-V3) after intravenous challenge with SHIV-89.6.

FIG. 6

Sequential plasma viral load measurements in rhesus monkeys immunized with a control peptide (C4/scbl-V3) or experimental homologous peptide (C4/89.6P) after intravenous challenge with SHIV-89.6P.

FIG. 7

Sequential peripheral blood CD4⁺ lymphocyte counts in rhesus monkeys immunized with a control peptide (C4/scbl-V3) or experimental homologous peptide (C4/89.6P) after intravenous challenge with SHIV-89.6P.