Passive immunization of macaques with polyclonal anti-SHIV IgG against a heterologous tier 2 SHIV

Outcome depends on IgG dose

Anton M. Sholukh, Siddappa Nagadenahalli 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. Polonis & 5 others Miroslawa Bilska, David C. Montefiori, Welkin E. Johnson, Hildegund C. Ertl, Ruth M. Ruprecht

Research output: Contribution to journalArticle

13 Citations (Scopus)

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

Fingerprint

Passive Immunization
Macaca
HIV-1
Immunoglobulin G
Neutralizing Antibodies
Macaca mulatta
Viruses
Primates
AIDS Vaccines
Viremia
Natural Killer Cells
Vaccines
HIV
Genome
anti-IgG
Infection
Population
In Vitro Techniques

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

Cite this

Sholukh, A. M., Byrareddy, S. N., Shanmuganathan, V., Hemashettar, G., Lakhashe, S. K., Rasmussen, R. A., ... 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

Passive immunization of macaques with polyclonal anti-SHIV IgG against a heterologous tier 2 SHIV : Outcome depends on IgG dose. / Sholukh, Anton M.; Byrareddy, Siddappa Nagadenahalli; Shanmuganathan, Vivekanandan; Hemashettar, Girish; Lakhashe, Samir K.; Rasmussen, Robert A.; Watkins, Jennifer D.; Vyas, Hemant K.; Thorat, Swati; Brandstoetter, Tania; Mukhtar, Muhammad M.; Yoon, John K.; Novembre, Francis J.; Villinger, Francois; Landucci, Gary; Forthal, Donald N.; Ratcliffe, Sarah; Tuero, Iskra; Robert-Guroff, Marjorie; Polonis, Victoria R.; Bilska, Miroslawa; Montefiori, David C.; Johnson, Welkin E.; Ertl, Hildegund C.; Ruprecht, Ruth M.

In: Retrovirology, Vol. 11, No. 1, 8, 20.01.2014.

Research output: Contribution to journalArticle

Sholukh, AM, Byrareddy, SN, Shanmuganathan, V, Hemashettar, G, Lakhashe, SK, Rasmussen, RA, Watkins, JD, Vyas, HK, Thorat, S, Brandstoetter, T, Mukhtar, MM, Yoon, JK, Novembre, FJ, Villinger, F, Landucci, G, Forthal, DN, Ratcliffe, S, Tuero, I, Robert-Guroff, M, Polonis, VR, Bilska, M, Montefiori, DC, Johnson, WE, Ertl, HC & Ruprecht, RM 2014, 'Passive immunization of macaques with polyclonal anti-SHIV IgG against a heterologous tier 2 SHIV: Outcome depends on IgG dose', Retrovirology, vol. 11, no. 1, 8. https://doi.org/10.1186/1742-4690-11-8
Sholukh, Anton M. ; Byrareddy, Siddappa Nagadenahalli ; Shanmuganathan, Vivekanandan ; Hemashettar, Girish ; Lakhashe, Samir K. ; Rasmussen, Robert A. ; Watkins, Jennifer D. ; Vyas, Hemant K. ; Thorat, Swati ; Brandstoetter, Tania ; Mukhtar, Muhammad M. ; Yoon, John K. ; Novembre, Francis J. ; Villinger, Francois ; Landucci, Gary ; Forthal, Donald N. ; Ratcliffe, Sarah ; Tuero, Iskra ; Robert-Guroff, Marjorie ; Polonis, Victoria R. ; Bilska, Miroslawa ; Montefiori, David C. ; Johnson, Welkin E. ; Ertl, Hildegund C. ; Ruprecht, Ruth M. / Passive immunization of macaques with polyclonal anti-SHIV IgG against a heterologous tier 2 SHIV : Outcome depends on IgG dose. In: Retrovirology. 2014 ; Vol. 11, No. 1.
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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.",
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T1 - Passive immunization of macaques with polyclonal anti-SHIV IgG against a heterologous tier 2 SHIV

T2 - Outcome depends on IgG dose

AU - Sholukh, Anton M.

AU - Byrareddy, Siddappa Nagadenahalli

AU - Shanmuganathan, Vivekanandan

AU - Hemashettar, Girish

AU - Lakhashe, Samir K.

AU - Rasmussen, Robert A.

AU - Watkins, Jennifer D.

AU - Vyas, Hemant K.

AU - Thorat, Swati

AU - Brandstoetter, Tania

AU - Mukhtar, Muhammad M.

AU - Yoon, John K.

AU - Novembre, Francis J.

AU - Villinger, Francois

AU - Landucci, Gary

AU - Forthal, Donald N.

AU - Ratcliffe, Sarah

AU - Tuero, Iskra

AU - Robert-Guroff, Marjorie

AU - Polonis, Victoria R.

AU - Bilska, Miroslawa

AU - Montefiori, David C.

AU - Johnson, Welkin E.

AU - Ertl, Hildegund C.

AU - Ruprecht, Ruth M.

PY - 2014/1/20

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N2 - 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.

AB - 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.

KW - Enhancement of infection

KW - Heterologous R5 SHIV clade C challenge

KW - Macaque model

KW - Non-human primate model

KW - Passive immunization

KW - SHIVIG

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