RAPID DEVELOPMENT OF GLYCAN-SPECIFIC, BROAD AND POTENT ANTI-HIV 1 GP120 NEUTRALIZING ANTIBODIES IN A SHIV- INFECTED MACAQUE. It is widely believed that the induction of a broadly neutralizing antibody (bNAb) response will be a critical component of a successful vaccine against HIV. A significant fraction of HIV-infected individuals mount bNAb responses, providing support for the notion that such responses could be elicited through vaccination. SIV and SHIV-infection of macaques have been widely used to model aspects of HIV infection but to date only rather limited bNAb responses have been observed in these animal models. In collaboration with Dennis Burton, Scripps Research Institute, we screened plasma from 14 SHIVAD8-infected macaques for cross-reacting neutralizing activity. One macaque displayed extraordinarily potent cross-clade plasma NAb responses against multiple Tier 2 HIV-1 isolates. Neutralization assays performed on plasma samples taken at serial time points from this animal revealed that broad and potent plasma neutralizing activity developed rapidly and coincided with the development of autologous NAb responses. Serum mapping studies were carried out using pseudovirus point mutants and antigen adsorption assays, and indicated that the plasma bNAbs are specific for carbohydrate epitopes critically dependent on the glycan at position 332 of Env gp120. These results provide insight into the development and evolution of broad anti-HIV-1 responses, suggest that certain bNAb specificities can be more rapidly induced by immunization than others, and validate the use of the macaque model to assess the potency of vaccine candidates. PATHOGENICITY AND MUCOSAL TRANSMISSIBILITY OF R5-TROPIC SIMIAN/HUMAN IMMUNODEFICIENCY VIRUSES SHIVAD8 IN RHESUS MACAQUES: IMPLICATIONS FOR THEIR USE IN VACCINE STUDIES. We have prepared swarm SHIVAD8 stocks from three different infected rhesus macaques at the time of euthanasia with documented immunodeficiency and have characterized each for their capacity to establish durable infections in macaques following inoculation by the intravenous (IV) or intrarectal (IR) routes. All three viral stocks (SHIVAD8-CE8J, SHIVAD8-CK15 and SHIVAD8-CL98) exhibited robust replication in vivo and caused marked depletion of CD4+ T cells affecting both memory and nave CD4+ T lymphocyte subsets, following either route of administration. Eleven of 22 macaques inoculated with the new SHIVAD8 stocks were euthanized with clinical symptoms of immunodeficiency and evidence of opportunistic infections (Pneumocystis, Candida and Mycobacterium). A single but unique founder virus, also present in the SHIVAD8-CE8J swarm stock, was transmitted to two animals following a single IR inoculation of approximately 3 animal infectious doses, which is close to the threshold required to establish infection in all exposed animals. Because the three new SHIVAD8 viruses are mucosally transmissible, exhibited Tier 2 sensitivity to anti-HIV 1 neutralizing antibodies, deplete CD4+ T lymphocytes in vivo, and induce AIDS in macaques, they are eminently suitable as challenge viruses in vaccine experiments. MOST RHESUS MACAQUES INFECTED WITH THE R5-TROPIC SHIVAD8 GENERATE CROSS-REACTIVE ANTIBODIES THAT NEUTRALIZE MULTIPLE HIV 1 STRAINS. A major challenge in HIV vaccine research has been the development of immunogens capable of eliciting potent, broadly acting, neutralizing antibodies (NAbs). Characterization of a new pathogenic R5-tropic SHIVAD8 molecular clone (SHIVAD8-EO) revealed that 8 of 8 infected animals developed cross-reactive neutralizing antibodies (NAbs) directed against an envelope glycoprotein derived from the heterologous HIV 1DH12 strain. A panel of plasmas, collected from monkeys inoculated with either molecularly cloned or uncloned SHIVAD8 stocks, exhibited cross neutralization against multiple tier 1 and tier 2 HIV 1 clade B isolates. One SHIVAD8 infected animal also developed NAbs against clade A and C HIV 1 strains. In this particular infected macaque, the cross-reacting anti-HIV 1 NAbs produced between weeks 7 to 13 were directed against a neutralization sensitive virus strain, whereas neutralizing activities emerging at weeks 41 to 51 targeted more neutralization resistant HIV 1 isolates. These results indicate that the SHIVAD8 macaque model represents a potentially valuable experimental system for investigating B cell maturation and the induction of cross-reactive NAbs directed against multiple HIV 1 strains.

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Gautam, Rajeev; Nishimura, Yoshiaki; Pegu, Amarendra et al. (2016) A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature 533:105-9
Francica, Joseph R; Sheng, Zizhang; Zhang, Zhenhai et al. (2015) Analysis of immunoglobulin transcripts and hypermutation following SHIV(AD8) infection and protein-plus-adjuvant immunization. Nat Commun 6:6565
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Walker, Laura M; Sok, Devin; Nishimura, Yoshiaki et al. (2011) Rapid development of glycan-specific, broad, and potent anti-HIV-1 gp120 neutralizing antibodies in an R5 SIV/HIV chimeric virus infected macaque. Proc Natl Acad Sci U S A 108:20125-9
Klatt, N R; Harris, L D; Vinton, C L et al. (2010) Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection. Mucosal Immunol 3:387-98
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