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. ANALYSIS OF IMMUNOGLOBULIN TRANSCRIPTS AND HYPERMUTATION FOLLOWING SHIV(AD8) INFECTION OR PROTEIN-PLUS-ADJUVANT IMMUNIZATION. Using a high-throughput NGS platform with a newly generated draft Rhesus macaque Ig HC reference database, Env-specific antibody responses were assessed following SHIVAD8 infection and Env protein-plus-adjuvant vaccination to gain insight into factors that influence somatic hyper mutation (SHM) and other characteristics associated with neutralizing antibodies. The SHIVAD8 infection model provides a striking contrast in the amount, duration, diversity and conformation of Env antigen compared with homologous Env protein immunization. Nevertheless, it was notable that antigen-specific B cells in both SHIVAD8-infected and Env-vaccinated animals had similar mean germline divergence levels at both week 6 and week 26. As the SHIVAD8 infection progressed past week 50, animals that maintained their viral loads had increased viral diversity and increased antibody germline divergence, which was associated with the development of cross-reactive neutralization. These data are consistent with several studies of HIV-infected individuals in whom increased viral loads and viral Env diversity were correlated with serum neutralization capacity. By contrast, and consistent with other gp140 vaccination studies, Env-vaccinated NHP did not develop significant cross-reactive neutralization responses. Of note, sequences greater than 20% divergent from germline (which is in the range of many characterized bNAbs5) were detected from some animals in all vaccine groups after four immunizations. These data show that levels of SHM accumulated following infection or vaccination may be necessary but are not sufficient to generate potent cross-reactive neutralization.
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