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. 2010 Sep;84(18):9086-95.
doi: 10.1128/JVI.01015-10. Epub 2010 Jul 7.

Immunization with wild-type or CD4-binding-defective HIV-1 Env trimers reduces viremia equivalently following heterologous challenge with simian-human immunodeficiency virus

Christopher Sundling  1 , Sijy O'Dell, Iyadh Douagi, Mattias N Forsell, Andreas Mörner, Karin Loré, John R Mascola, Richard T Wyatt, Gunilla B Karlsson Hedestam
Affiliations

Immunization with wild-type or CD4-binding-defective HIV-1 Env trimers reduces viremia equivalently following heterologous challenge with simian-human immunodeficiency virus

Christopher Sundling et al. J Virol. 2010 Sep.

Abstract

We recently reported that rhesus macaques inoculated with CD4-binding-competent and CD4-binding-defective soluble YU2-derived HIV-1 envelope glycoprotein (Env) trimers in adjuvant generate comparable levels of Env-specific binding antibodies (Abs) and T cell responses. We also showed that Abs directed against the Env coreceptor binding site (CoRbs) were elicited only in animals immunized with CD4-binding-competent trimers and not in animals immunized with CD4-binding-defective trimers, indicating that a direct interaction between Env and CD4 occurs in vivo. To investigate both the overall consequences of in vivo Env-CD4 interactions and the elicitation of CoRbs-directed Abs for protection against heterologous simian-human immunodeficiency virus (SHIV) challenge, we exposed rhesus macaques immunized with CD4-binding-competent and CD4-binding-defective trimers to the CCR5-tropic SHIV-SF162P4 challenge virus. Compared to unvaccinated controls, all vaccinated animals displayed improved control of plasma viremia, independent of the presence or absence of CoRbs-directed Abs prior to challenge. Immunization resulted in plasma responses that neutralized the heterologous SHIV challenge stock in vitro, with similar neutralizing Ab titers elicited by the CD4-binding-competent and CD4-binding-defective trimers. The neutralizing responses against both the SHIV-SF162P4 stock and a recombinant virus pseudotyped with a cloned SHIV-SF162P4-derived Env were significantly boosted by the SHIV challenge. Collectively, these results suggest that the capacity of soluble Env trimers to interact with primate CD4 in vivo and to stimulate the production of moderate titers of CoRbs-directed Abs did not influence the magnitude of the neutralizing Ab recall response after viral challenge or the subsequent control of viremia in this heterologous SHIV challenge model.

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Figures

FIG. 1.
FIG. 1.
Immunogenic profiles of Env immunogens. (A) Schematic presentation of immunization, bleeds, and challenge of the Env trimer-immunized monkeys. (B) Pseudovirus neutralization of SF162 and MN as shown by plasma ID50 titer. Shown is neutralization at 2 weeks after immunizations 1 to 5. Error bars indicate standard errors of the means. (C) Coreceptor binding site Abs present in plasma samples from the immunized groups, as determined by the HIV-2 pseudovirus neutralization assay 2 weeks after immunization 5. (D) Log10 OD50 binding titers in plasma to the YU2 variable region 3 peptide, TRPNNNTRKSINIGPGRALYTTG, at 2 weeks after immunization 5.
FIG. 2.
FIG. 2.
SHIV-SF162P4 challenge. At 4 weeks after immunization 5, all three immunized animals (wt, 368, and 423/425/431; n = 5 per group) and a control group (n = 8) of naïve rhesus macaques were challenged intravenously with SHIV-SF162P4. (A) Kinetics of viral load. Viral loads were measured in plasma both prior to challenge (Pre) and at 1 to 10 weeks postchallenge (PC). The lower detection limit was set to 500 copies/ml. (B and C) Cumulative viral load as calculated from area under the curve (AUC) (B) and peak viral load (C) were determined for each animal. The data are shown for individual monkeys and as box plots. Statistical significance was evaluated with the Mann-Whitney U test. ns, not significant.
FIG. 3.
FIG. 3.
Anamnestic antibody responses. (A) Graph illustrating the anamnestic Ab responses to gp120 (left axis, solid lines) in comparison to viral load (right axis, dotted lines). (B) YU2 (black)- and SF162 (white)-specific Ab responses were determined for each group before challenge (Pre) and 1 to 10 weeks after challenge (PC). (C) Variable loop 3-directed Ab responses were evaluated as for gp120. Shown are means ± standard errors of the means of log10 OD50 binding titers (n = 5 for immunized animals and n = 8 for controls) Statistical significance was determined with repeated-measures two-way ANOVA.
FIG. 4.
FIG. 4.
Effect of anamnestic antibody response on neutralization. (A) Neutralization titers (ID50) of the parental SF162 and SHIV-SF162P4 clone 41.1 pseudoviruses and SHIV-SF162P4 replication-competent stock before challenge (Pre) and 4 weeks after challenge (PC). Shown are results for individual monkeys. Statistical significance was determined with two-way ANOVA. Monkey F77 was excluded from all postchallenge analysis as it did not become infected by the challenge virus. (B) Correlation between SF162 binding Abs and neutralization to SF162, SHIV-SF162P4 clone 41.1, and the SHIV-SF162P4 stock following the anamnestic response. Correlations were determined with the Spearman test.
FIG. 5.
FIG. 5.
Characterization of SHIV-SF162P4 neutralization sensitivity. Neutralizing titers (ID50) against the pseudoviruses SF162 and SHIV-SF162P4 clone 41.1 and the replication-competent SHIV-SF162P4 stock in plasma samples from immunized animals (wt, 368, and 423/425/431; n = 5 per group) was determined 2 weeks after immunization 5. Plasma was preincubated with YU2 V3 peptide or scrambled control peptide before being added to the neutralization assay mixture. Neutralization due to V3-directed Abs was calculated as fold reduction of ID50 in comparison to that for mock infection. Significance was evaluated with the Mann-Whitney U test.
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