Passive immunization of macaques with polyclonal anti-SHIV IgG against a heterologous tier 2 SHIV: Outcome depends on IgG dose

Anton M. Sholukh, Siddappa N. Byrareddy, Vivekanandan Shanmuganathan, Girish Hemashettar, Samir K. Lakhashe, Robert A. Rasmussen, Jennifer D. Watkins, Hemant K. Vyas, Swati Thorat, Tania Brandstoetter, Muhammad M. Mukhtar, John K. Yoon, Francis J. Novembre, Francois Villinger, Gary Landucci, Donald N. Forthal, Sarah Ratcliffe, Iskra Tuero, Marjorie Robert-Guroff, Victoria R. PolonisMiroslawa Bilska, David C. Montefiori, Welkin E. Johnson, Hildegund C. Ertl, Ruth M. Ruprecht

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Background: A key goal for HIV-1 envelope immunogen design is the induction of cross-reactive neutralizing antibodies (nAbs). As AIDS vaccine recipients will not be exposed to strains exactly matching any immunogens due to multiple HIV-1 quasispecies circulating in the human population worldwide, heterologous SHIV challenges are essential for realistic vaccine efficacy testing in primates. We assessed whether polyclonal IgG, isolated from rhesus monkeys (RMs) with high-titer nAbs (termed SHIVIG), could protect RMs against the R5-tropic tier-2 SHIV-2873Nip, which was heterologous to the viruses or HIV-1 envelopes that had elicited SHIVIG.Results: SHIVIG demonstrated binding to HIV Gag, Tat, and Env of different clades and competed with the broadly neutralizing antibodies b12, VRC01, 4E10, and 17b. SHIVIG neutralized tier 1 and tier 2 viruses, including SHIV-2873Nip. NK-cell depletion decreased the neutralizing activity of SHIVIG 20-fold in PBMC assays. Although SHIVIG neutralized SHIV-2873Nip in vitro, this polyclonal IgG preparation failed to prevent acquisition after repeated intrarectal low-dose virus challenges, but at a dose of 400 mg/kg, it significantly lowered peak viremia (P = 0.001). Unexpectedly, single-genome analysis revealed a higher number of transmitted variants at the low dose of 25 mg/kg, implying increased acquisition at low SHIVIG levels. In vitro, SHIVIG demonstrated complement-mediated Ab-dependent enhancement of infection (C'-ADE) at concentrations similar to those observed in plasmas of RMs treated with 25 mg/kg of SHIVIG.Conclusion: Our primate model data suggest a dual role for polyclonal anti-HIV-1 Abs depending on plasma levels upon virus encounter.

Original languageEnglish (US)
Article number8
JournalRetrovirology
Volume11
Issue number1
DOIs
StatePublished - Jan 20 2014

Keywords

  • Enhancement of infection
  • Heterologous R5 SHIV clade C challenge
  • Macaque model
  • Non-human primate model
  • Passive immunization
  • SHIVIG

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

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    Sholukh, A. M., Byrareddy, S. N., Shanmuganathan, V., Hemashettar, G., Lakhashe, S. K., Rasmussen, R. A., Watkins, J. D., Vyas, H. K., Thorat, S., Brandstoetter, T., Mukhtar, M. M., Yoon, J. K., Novembre, F. J., Villinger, F., Landucci, G., Forthal, D. N., Ratcliffe, S., Tuero, I., Robert-Guroff, M., ... Ruprecht, R. M. (2014). Passive immunization of macaques with polyclonal anti-SHIV IgG against a heterologous tier 2 SHIV: Outcome depends on IgG dose. Retrovirology, 11(1), [8]. https://doi.org/10.1186/1742-4690-11-8