PASSIVE TRANSFER OF MODEST TITERS OF POTENT AND BROADLY NEUTRALIZING ANTI-HIV MONOCLONAL ANTIBODIES BLOCK SHIV INFECTION IN MACAQUES. It is widely appreciated that effective human vaccines directed against viral pathogens elicit neutralizing antibodies (NAbs). The passive transfer of anti-HIV 1 NAbs conferring sterilizing immunity to macaques has been used to determine the plasma neutralization titers, which must be present at the time of exposure, to prevent acquisition of SIV/HIV chimeric virus (SHIV) infections. During the past four to five years, a new generation of potent broadly acting neutralizing mAbs have been isolated from HIV-1 infected individuals. These mAbs target the CD4 binding site (CD4bs), protein-glycan epitopes associated with the gp120 V1/V2, V3, and V4 regions, and the membrane proximal external region of gp41 and typically exhibit great breadth and potency against heterologous HIV-1 isolates when assayed for neutralization in vitro. In this study, five of the new neutralizing mAbs were individually administered to groups of rhesus macaques, which were subsequently separately challenged intrarectally with either of two different R5 SHIVs. Levels of HIV-1 NAbs in the blood and tissues were measured at the time of virus challenge. By combining the results obtained from 60 animals challenged with two different SHIVs, we determined that the plasma neutralization titer preventing virus acquisition was relatively modest (approximately 1:100) and potentially achievable by vaccination. These findings provide guidance for determining the levels of neutralizing activity in plasma that an effective HIV vaccine should elicit. NEXT-GENERATION SEQUENCING OF PERIPHERAL IMMUNOGLOBULIN TRANSCRIPTS REVEALS DIFFERENTIAL SOMATIC HYPERMUTATION FOLLOWING SHIVAD8 INFECTION AND HIV-1 ENVELOPE PROTEIN VACCINATION IN NONHUMAN PRIMATES. Developing predictive preclinical animal models to assess how candidate vaccines and infection influence the ontogenies of HIV Envelope (Env) broadly neutralizing antibodies will be critical for the development of a protective HIV vaccine. Such models should closely replicate human innate and adaptive responses to HIV infection and adjuvant vaccination. Here we performed a comprehensive longitudinal analysis in nonhuman primates (NHP) of HIV Env-specific B cell receptor responses to pathogenic SHIVAD8 infection and Env protein vaccination with 8 different adjuvants to compare and contrast the role of antigen persistence, diversity and innate immunity. A new draft database of the rhesus macaque germline immunoglobulin heavy-chain locus was used to interrogate antibody responses bioinformatically. A subset of the SHIVAD8-infected animals with higher viral loads and greater Env diversity showed increased neutralization potency and breadth associated with higher SHM levels over time. Following 4 Env protein immunizations, adjuvants increased antibody titers compared to protein alone, but did not improve mean SHM levels or alter CDR H3 length. These complementary models provide a mechanism to track the ontogeny of Env-specific B cell immunity and should facilitate translation between NHP and human vaccine studies
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