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

Anton M Sholukh123, Siddappa N Byrareddy236, Vivekanandan Shanmuganathan2, Girish Hemashettar2, Samir K Lakhashe123, Robert A Rasmussen23, Jennifer D Watkins23, Hemant K Vyas123, Swati Thorat23, Tania Brandstoetter2, Muhammad M Mukhtar123, John K Yoon2, Francis J Novembre45, Francois Villinger46, Gary Landucci7, Donald N Forthal7, Sarah Ratcliffe8, Iskra Tuero9, Marjorie Robert-Guroff9, Victoria R Polonis10, Miroslawa Bilska11, David C Montefiori11, Welkin E Johnson12, Hildegund C Ertl13 and Ruth M Ruprecht123*

Author Affiliations

1 Department of Virology and Immunology, Texas Biomedical Research Institute, PO Box 760549, San Antonio, TX 78245-0549, USA

2 Dana-Farber Cancer Institute, Boston, MA, USA

3 Harvard Medical School, Boston, MA, USA

4 Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA

5 Department of Microbiology and Immunology and Laboratory Medicine, Emory University, Atlanta, GA, USA

6 Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA

7 Division of Infectious Diseases, Department of Medicine, University of California, Irvine School of Medicine, Irvine, CA, USA

8 Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

9 National Cancer Institute, Center for Cancer Research, Vaccine Branch, Bethesda, MD, USA

10 The Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA

11 Department of Surgery, Duke University School of Medicine, Durham, NC, USA

12 Department of Biology, Boston College, Boston, MA, USA

13 The Wistar Institute, Philadelphia, Pennsylvania, USA

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Retrovirology 2014, 11:8  doi:10.1186/1742-4690-11-8

Published: 20 January 2014

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 (Pā€‰=ā€‰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 (Cā€™-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.

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