An anti-HIV-1 V3 loop antibody fully protects cross-clade and elicits T-cell immunity in macaques mucosally challenged with an R5 clade C SHIV

Jennifer D. Watkins, Nagadenahalli B. Siddappa, Samir K. Lakhashe, Michael Humbert, Anton Sholukh, Girish Hemashettar, Yin Ling Wong, John K. Yoon, Wendy Wang, Francis J. Novembre, Francois Villinger, Chris Ibegbu, Kalpana Patel, Davide Corti, Gloria Agatic, Fabrizia Vanzetta, Siro Bianchi, Jonathan L. Heeney, Federica Sallusto, Antonio LanzavecchiaRuth M. Ruprecht

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Neutralizing antibodies have been shown to protect macaques against SHIV challenge. However, genetically diverse HIV-1 clades have evolved, and a key question left unanswered is whether neutralizing antibodies can confer cross-clade protection in vivo. The novel human monoclonal antibody HGN194 was isolated from an individual infected with an HIV-1 clade AG recombinant circulating recombinant form (CRF). HGN194 targets an epitope in the third hypervariable loop (V3) of HIV-1 gp120 and neutralizes a range of relatively neutralization-sensitive and resistant viruses. We evaluated the potential of HGN194 to protect infant rhesus monkeys against a SHIV encoding a primary CCR5-tropic HIV-1 clade C envelope. After high-dose mucosal challenge, all untreated controls became highly viremic while all HGN194-treated animals (50 mg/kg) were completely protected. When HGN194 was given at 1 mg/kg, one out of two monkeys remained aviremic, whereas the other had delayed, lower peak viremia. Interestingly, all protected monkeys given high-dose HGN194 developed Gag-specific proliferative responses of both CD4+ and CD8+ T cells. To test whether generation of the latter involved cryptic infection, we ablated CD8+ cells after HGN194 clearance. No viremia was detected in any protected monkeys, thus ruling out virus reservoirs. Thus, induction of CD8 T-cell immunity may have resulted from transient "Hit and Run" infection or cross priming via Ag-Ab-mediated cross-presentation. Together, our data identified the HGN194 epitope as protective and provide proof-of-concept that this anti-V3 loop mAb can prevent infection with sterilizing immunity after challenge with virus of a different clade, implying that V3 is a potential vaccine target.

Original languageEnglish (US)
Article numbere18207
JournalPloS one
Volume6
Issue number3
DOIs
StatePublished - Apr 8 2011

Fingerprint

T-cells
Macaca
Human immunodeficiency virus 1
Viruses
HIV-1
Immunity
T-lymphocytes
immunity
Cross-Priming
Neutralizing Antibodies
Haplorhini
monkeys
T-Lymphocytes
antibodies
Antibodies
Epitopes
Viremia
viremia
neutralizing antibodies
viruses

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

An anti-HIV-1 V3 loop antibody fully protects cross-clade and elicits T-cell immunity in macaques mucosally challenged with an R5 clade C SHIV. / Watkins, Jennifer D.; Siddappa, Nagadenahalli B.; Lakhashe, Samir K.; Humbert, Michael; Sholukh, Anton; Hemashettar, Girish; Wong, Yin Ling; Yoon, John K.; Wang, Wendy; Novembre, Francis J.; Villinger, Francois; Ibegbu, Chris; Patel, Kalpana; Corti, Davide; Agatic, Gloria; Vanzetta, Fabrizia; Bianchi, Siro; Heeney, Jonathan L.; Sallusto, Federica; Lanzavecchia, Antonio; Ruprecht, Ruth M.

In: PloS one, Vol. 6, No. 3, e18207, 08.04.2011.

Research output: Contribution to journalArticle

Watkins, JD, Siddappa, NB, Lakhashe, SK, Humbert, M, Sholukh, A, Hemashettar, G, Wong, YL, Yoon, JK, Wang, W, Novembre, FJ, Villinger, F, Ibegbu, C, Patel, K, Corti, D, Agatic, G, Vanzetta, F, Bianchi, S, Heeney, JL, Sallusto, F, Lanzavecchia, A & Ruprecht, RM 2011, 'An anti-HIV-1 V3 loop antibody fully protects cross-clade and elicits T-cell immunity in macaques mucosally challenged with an R5 clade C SHIV', PloS one, vol. 6, no. 3, e18207. https://doi.org/10.1371/journal.pone.0018207
Watkins, Jennifer D. ; Siddappa, Nagadenahalli B. ; Lakhashe, Samir K. ; Humbert, Michael ; Sholukh, Anton ; Hemashettar, Girish ; Wong, Yin Ling ; Yoon, John K. ; Wang, Wendy ; Novembre, Francis J. ; Villinger, Francois ; Ibegbu, Chris ; Patel, Kalpana ; Corti, Davide ; Agatic, Gloria ; Vanzetta, Fabrizia ; Bianchi, Siro ; Heeney, Jonathan L. ; Sallusto, Federica ; Lanzavecchia, Antonio ; Ruprecht, Ruth M. / An anti-HIV-1 V3 loop antibody fully protects cross-clade and elicits T-cell immunity in macaques mucosally challenged with an R5 clade C SHIV. In: PloS one. 2011 ; Vol. 6, No. 3.
@article{acc7434053c44c9ba740e165aeaeb40a,
title = "An anti-HIV-1 V3 loop antibody fully protects cross-clade and elicits T-cell immunity in macaques mucosally challenged with an R5 clade C SHIV",
abstract = "Neutralizing antibodies have been shown to protect macaques against SHIV challenge. However, genetically diverse HIV-1 clades have evolved, and a key question left unanswered is whether neutralizing antibodies can confer cross-clade protection in vivo. The novel human monoclonal antibody HGN194 was isolated from an individual infected with an HIV-1 clade AG recombinant circulating recombinant form (CRF). HGN194 targets an epitope in the third hypervariable loop (V3) of HIV-1 gp120 and neutralizes a range of relatively neutralization-sensitive and resistant viruses. We evaluated the potential of HGN194 to protect infant rhesus monkeys against a SHIV encoding a primary CCR5-tropic HIV-1 clade C envelope. After high-dose mucosal challenge, all untreated controls became highly viremic while all HGN194-treated animals (50 mg/kg) were completely protected. When HGN194 was given at 1 mg/kg, one out of two monkeys remained aviremic, whereas the other had delayed, lower peak viremia. Interestingly, all protected monkeys given high-dose HGN194 developed Gag-specific proliferative responses of both CD4+ and CD8+ T cells. To test whether generation of the latter involved cryptic infection, we ablated CD8+ cells after HGN194 clearance. No viremia was detected in any protected monkeys, thus ruling out virus reservoirs. Thus, induction of CD8 T-cell immunity may have resulted from transient {"}Hit and Run{"} infection or cross priming via Ag-Ab-mediated cross-presentation. Together, our data identified the HGN194 epitope as protective and provide proof-of-concept that this anti-V3 loop mAb can prevent infection with sterilizing immunity after challenge with virus of a different clade, implying that V3 is a potential vaccine target.",
author = "Watkins, {Jennifer D.} and Siddappa, {Nagadenahalli B.} and Lakhashe, {Samir K.} and Michael Humbert and Anton Sholukh and Girish Hemashettar and Wong, {Yin Ling} and Yoon, {John K.} and Wendy Wang and Novembre, {Francis J.} and Francois Villinger and Chris Ibegbu and Kalpana Patel and Davide Corti and Gloria Agatic and Fabrizia Vanzetta and Siro Bianchi and Heeney, {Jonathan L.} and Federica Sallusto and Antonio Lanzavecchia and Ruprecht, {Ruth M.}",
year = "2011",
month = "4",
day = "8",
doi = "10.1371/journal.pone.0018207",
language = "English (US)",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - An anti-HIV-1 V3 loop antibody fully protects cross-clade and elicits T-cell immunity in macaques mucosally challenged with an R5 clade C SHIV

AU - Watkins, Jennifer D.

AU - Siddappa, Nagadenahalli B.

AU - Lakhashe, Samir K.

AU - Humbert, Michael

AU - Sholukh, Anton

AU - Hemashettar, Girish

AU - Wong, Yin Ling

AU - Yoon, John K.

AU - Wang, Wendy

AU - Novembre, Francis J.

AU - Villinger, Francois

AU - Ibegbu, Chris

AU - Patel, Kalpana

AU - Corti, Davide

AU - Agatic, Gloria

AU - Vanzetta, Fabrizia

AU - Bianchi, Siro

AU - Heeney, Jonathan L.

AU - Sallusto, Federica

AU - Lanzavecchia, Antonio

AU - Ruprecht, Ruth M.

PY - 2011/4/8

Y1 - 2011/4/8

N2 - Neutralizing antibodies have been shown to protect macaques against SHIV challenge. However, genetically diverse HIV-1 clades have evolved, and a key question left unanswered is whether neutralizing antibodies can confer cross-clade protection in vivo. The novel human monoclonal antibody HGN194 was isolated from an individual infected with an HIV-1 clade AG recombinant circulating recombinant form (CRF). HGN194 targets an epitope in the third hypervariable loop (V3) of HIV-1 gp120 and neutralizes a range of relatively neutralization-sensitive and resistant viruses. We evaluated the potential of HGN194 to protect infant rhesus monkeys against a SHIV encoding a primary CCR5-tropic HIV-1 clade C envelope. After high-dose mucosal challenge, all untreated controls became highly viremic while all HGN194-treated animals (50 mg/kg) were completely protected. When HGN194 was given at 1 mg/kg, one out of two monkeys remained aviremic, whereas the other had delayed, lower peak viremia. Interestingly, all protected monkeys given high-dose HGN194 developed Gag-specific proliferative responses of both CD4+ and CD8+ T cells. To test whether generation of the latter involved cryptic infection, we ablated CD8+ cells after HGN194 clearance. No viremia was detected in any protected monkeys, thus ruling out virus reservoirs. Thus, induction of CD8 T-cell immunity may have resulted from transient "Hit and Run" infection or cross priming via Ag-Ab-mediated cross-presentation. Together, our data identified the HGN194 epitope as protective and provide proof-of-concept that this anti-V3 loop mAb can prevent infection with sterilizing immunity after challenge with virus of a different clade, implying that V3 is a potential vaccine target.

AB - Neutralizing antibodies have been shown to protect macaques against SHIV challenge. However, genetically diverse HIV-1 clades have evolved, and a key question left unanswered is whether neutralizing antibodies can confer cross-clade protection in vivo. The novel human monoclonal antibody HGN194 was isolated from an individual infected with an HIV-1 clade AG recombinant circulating recombinant form (CRF). HGN194 targets an epitope in the third hypervariable loop (V3) of HIV-1 gp120 and neutralizes a range of relatively neutralization-sensitive and resistant viruses. We evaluated the potential of HGN194 to protect infant rhesus monkeys against a SHIV encoding a primary CCR5-tropic HIV-1 clade C envelope. After high-dose mucosal challenge, all untreated controls became highly viremic while all HGN194-treated animals (50 mg/kg) were completely protected. When HGN194 was given at 1 mg/kg, one out of two monkeys remained aviremic, whereas the other had delayed, lower peak viremia. Interestingly, all protected monkeys given high-dose HGN194 developed Gag-specific proliferative responses of both CD4+ and CD8+ T cells. To test whether generation of the latter involved cryptic infection, we ablated CD8+ cells after HGN194 clearance. No viremia was detected in any protected monkeys, thus ruling out virus reservoirs. Thus, induction of CD8 T-cell immunity may have resulted from transient "Hit and Run" infection or cross priming via Ag-Ab-mediated cross-presentation. Together, our data identified the HGN194 epitope as protective and provide proof-of-concept that this anti-V3 loop mAb can prevent infection with sterilizing immunity after challenge with virus of a different clade, implying that V3 is a potential vaccine target.

UR - http://www.scopus.com/inward/record.url?scp=79953653241&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953653241&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0018207

DO - 10.1371/journal.pone.0018207

M3 - Article

C2 - 21483815

AN - SCOPUS:79953653241

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 3

M1 - e18207

ER -