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.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Watkins
authors.forename: Nagadenahalli B
authors.initials: NB
authors.lastname: Siddappa
authors.forename: Samir K
authors.initials: SK
authors.lastname: Lakhashe
authors.forename: Michael
authors.initials: M
authors.lastname: Humbert
authors.forename: Anton
authors.initials: A
authors.lastname: Sholukh
authors.forename: Girish
authors.initials: G
authors.lastname: Hemashettar
authors.forename: Yin Ling
authors.initials: YL
authors.lastname: Wong
authors.forename: John K
authors.initials: JK
authors.lastname: Yoon
authors.forename: Wendy
authors.initials: W
authors.lastname: Wang
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Novembre
authors.forename: Francois
authors.initials: F
authors.lastname: Villinger
authors.forename: Chris
authors.initials: C
authors.lastname: Ibegbu
authors.forename: Kalpana
authors.initials: K
authors.lastname: Patel
authors.forename: Davide
authors.initials: D
authors.lastname: Corti
authors.forename: Gloria
authors.initials: G
authors.lastname: Agatic
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Vanzetta
authors.forename: Siro
authors.initials: S
authors.lastname: Bianchi
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Heeney
authors.forename: Federica
authors.initials: F
authors.lastname: Sallusto
authors.forename: Antonio
authors.initials: A
authors.lastname: Lanzavecchia
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Ruprecht
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D015483:HIV Antibodies / Q000276:immunology*; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D008251:Macaca; D008253:Macaca mulatta; D012367:RNA, Viral / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015483:HIV Antibodies; D012367:RNA, Viral