Virological Control by the CD4-Binding Site Antibody N6 in Simian-Human Immunodeficiency Virus-Infected Rhesus Monkeys.

TitleVirological Control by the CD4-Binding Site Antibody N6 in Simian-Human Immunodeficiency Virus-Infected Rhesus Monkeys.
Publication TypeJournal Article
Year of Publication2017
AuthorsJulg B, Pegu A, Abbink P, Liu J, Brinkman A, Molloy K, Mojta S, Chandrashekar A, Callow K, Wang K, Chen X, Schmidt SD, Huang J, Koup RA, Seaman MS, Keele BF, Mascola JR, Connors M, Barouch DH
JournalJ Virol
Volume91
Issue16
Paginationpii: e00498-17
Date Published08/15/2017
ISSN1098-5514
KeywordsAnimals, Antibodies, Neutralizing, Antiviral Agents, HIV Antibodies, Immunization, Passive, Macaca mulatta, Simian Acquired Immunodeficiency Syndrome, Simian immunodeficiency virus, Treatment Outcome, Viral Load
Abstract

Passive immunotherapy against HIV-1 will most likely require broadly neutralizing antibodies (bnAbs) with maximum breadth and potency to ensure therapeutic efficacy. Recently, the novel CD4 binding site antibody N6 demonstrated extraordinary neutralization breadth and potency against large panels of cross-clade pseudoviruses. We evaluated the in vivo antiviral activity of N6-LS, alone or in combination with the established V3-glycan antibody PGT121, in chronically simian-human immunodeficiency virus (SHIV)-SF162P3-infected macaques. A single dose of N6-LS suppressed plasma viral loads in 4 out of 5 animals at day 7, while the combination of both antibodies suppressed all animals. The combination of both antibodies had no additive antiviral effect compared to a single dose of PGT121, potentially reflecting the nearly 10-fold-higher potency of PGT121 against this SHIV. Viral rebound occurred in the majority of suppressed animals and was linked to declining plasma bnAb levels over time. In addition to the effect on plasma viremia, bnAb administration resulted in significantly reduced proviral DNA levels in PBMCs after 2 weeks and in lymph nodes after 10 weeks. Autologous neutralizing antibody (nAb) responses and CD8(+) T-cell responses were not significantly enhanced in the bnAb-treated animals compared to control animals, arguing against their contribution to the viral effects observed. These results confirm the robust antiviral activity of N6-LS in vivo, supporting the further clinical development of this antibody.IMPORTANCE Monocloncal antibodies (MAbs) are being considered for passive immunotherapy of HIV-1 infection. A critical requirement for such strategies is the identification of MAbs that recognize the diversity of variants within circulating but also reservoir viruses, and MAb combinations might be needed to achieve this goal. This study evaluates the novel bnAb N6-LS alone or in combination with the bnAb PGT121, in rhesus macaques that were chronically infected with SHIV. The results demonstrate that N6-LS potently suppressed plasma viral loads in the majority of animals but that the combination with PGT121 was not superior to PGT121 alone in delaying time to viral rebound or reducing peripheral blood mononuclear cell (PBMC) or lymph node proviral DNA levels. The occurrence of viral escape variants in an N6-LS-monotreated animal, however, argues for the need to maximize breadth and antiviral efficacy by combining bnAbs for therapeutic indications.

DOI10.1128/JVI.00498-17
Alternate JournalJ. Virol.
PubMed ID28539448
PubMed Central IDPMC5533891
Grant ListUM1 AI100663 / AI / NIAID NIH HHS / United States
UM1 AI126603 / AI / NIAID NIH HHS / United States
U19 AI096040 / AI / NIAID NIH HHS / United States
UM1 AI124377 / AI / NIAID NIH HHS / United States
HHSN261200800001C / RC / CCR NIH HHS / United States
K08 AI106408 / AI / NIAID NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
CHAVI-ID: 
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