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Efficacy of HIV-1 Monoclonal Antibody Immunotherapy in Acute SHIV-Infected Macaques
Diane L. Bolton1, Amarendra Pegu2, Keyun Wang2, Kathleen McGinnis2, Kathryn Foulds2, Srinivas Rao2, Merlin L. Robb1, Nelson L. Michael1, John Mascola2, Richard A. Koup2
1 US Military HIV Research Program, Silver Spring, MD, United States. 2 National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD, United States.
Background: Highly potent broadly neutralizing HIV-1 antibodies (bNAb) can suppress viremia in both humanized mouse and macaque models of HIV-1 infection. However, the therapeutic potential of these antibodies during early acute infection (e.g. Fiebig I-III) is unknown. Recent clinical evidence indicates that antiretroviral therapy (ART) administered during this period suppresses both viremia and seeding of the viral reservoir. Here we test the ability of bNAb regimens to control acute simian-human immunodeficiency virus (SHIV) replication in rhesus macaques and compare efficacy to ART.
Methods: Rhesus macaques were infected with SHIV-SF162P3 followed by administration 10 days later of either 1) daily triple drug ART; 2) a single dose of Env CD4-binding site specific bNAb, VRC01; 3) a single dose of a combination of a more potent clonal relative of VRC01 (VRC07-523) and a V1/V2 glycan-dependent bNAb (PGT121); or 4) no treatment. Daily ART was initiated 11 days after bNAb. Plasma viremia and cell-associated viral load were measured to assess efficacy.
Results: A single infusion of VRC01 on day 10 reduced viremia by ~ 1 log10 over the next 10 days. The combination of VRC07 and PGT121 had a greater effect of between 2 and 3 log10 that was similar to treatment with ART. Following peak viremia, control was better sustained by the dual bNAb and ART regimens than the VRC01 regimen. Plasma bNAb concentrations exceeded IC80 values for at least 7 days in all animals. Proviral DNA in lymph node was also diminished after treatment with ART or dual bNAb, both effecting a ~1 log decline in SHIV copies per CD4+ T cell. Decreased viral replication by these regimens was further evidenced by dampened cellular and humoral immune responses to viral antigens. Greater efficacy of VRC07-523 / PGT121 relative to VRC01 is consistent with more potent neutralization activity of these bNAbs against the SHIV-SF162P3 challenge virus.
Conclusions: Our findings demonstrate that potent neutralizing HIV-1-specific antibodies are at least as effective as ART at controlling acute virus replication. Moreover, bNAb immunotherapy may offer an advantage over ART in its ability to further reduce the proviral DNA burden. These data support future therapeutic clinical trials that investigate VRC01, and eventually other antibodies, as an alternative to or in conjunction with ART to treat Fiebig I-III HIV-1 infection.