The expanding HIV-1 pandemic, and the failure of human efficacy trials of T-cell and antibody-based vaccines, highlight the major gaps in knowledge that must be filled in order to pursue rational HIV-1 vaccine design and development. One of the most important knowiedge gaps relates to the precise nature of early virus-host interactions that lead to virus transmission and productive clinical infection. This application is a new HIVRAD proposal by investigators whose recent scientific discoveries relate directly to this priority area of research. These discoveries - the identification of transmitted/founder HIV-1 and SIV genomes (Keele 2008;Keele 2009;Salazar 2009), the identification of genetically-divergent SIVsmm strains in naturallyinfected sooty mangabeys (Apetrei 2005;Apetrei 2007), and the identification of innate mucosal immune responses modulating early virus-host interactions (Estes 2006;Estes 2008;Li 2009) - create a unique and timely opportunity to focus three cutting edge research themes on a high priority HIV/SIV vaccine research problem. The current proposal is comprised of three interrelated projects and two cores led by investigators at the University of Alabama at Birmingham (Shaw and Hahn);the University of Pittsburgh (Apetrei and Pandrea);and NCI-Frederick (Estes, Keele and Lifson). Project #1 is "Mucosal transmission and pathogenicity of novel SIVsmm virus strains (Apetrei)." Project #2 is "Identification, cloning and characterization of transmitted/founder SIVsmm (Hahn)." Project #3 is "Molecular analysis of the mucosal SIVsmm transmission bottleneck (Shaw)." Collectively, the projects will test this hypothesis: Identification, molecular cloning, and in vivo analysis of naturally-occurring mucosally-transmitted strains of SIVsmm corresponding to transmitted/founder viruses will reveal viral-host interactions responsible for selective SIV transmission across rectal, vaginal and cervical mucosa and will provide novel, genetically-divergent, pathogenic virus challenge strains for vaccine testing. A key deliverable of this research to the SIV/HIV vaccine field, in addition to new scientific insights into mucosal transmission, will be 18 molecular clones of transmitted/founder viruses representing three widely divergent SIVsmm genetic lineages for use as potential challenge stocks.
The expanding HIV-1 pandemic, and the failure of human clinical trials of T-cell and antibody-based vaccines, highlight gaps in scientific knowledge about the initial steps in virus transmission and vaccine approaches to prevent infection. This project will identify and clone new, naturally occurring strains of SIVsmm and will use these to elucidate early infection events in the SIV-rhesus macaque model of human HIV-1 infection.
|Smedley, Jeremy; Turkbey, Baris; Bernardo, Marcelino L et al. (2014) Tracking the luminal exposure and lymphatic drainage pathways of intravaginal and intrarectal inocula used in nonhuman primate models of HIV transmission. PLoS One 9:e92830|
|Ma, Dongzhu; Jasinska, Anna J; Feyertag, Felix et al. (2014) Factors associated with siman immunodeficiency virus transmission in a natural African nonhuman primate host in the wild. J Virol 88:5687-705|
|Roederer, Mario; Keele, Brandon F; Schmidt, Stephen D et al. (2014) Immunological and virological mechanisms of vaccine-mediated protection against SIV and HIV. Nature 505:502-8|
|Ma, Dongzhu; Jasinska, Anna; Kristoff, Jan et al. (2013) SIVagm infection in wild African green monkeys from South Africa: epidemiology, natural history, and evolutionary considerations. PLoS Pathog 9:e1003011|
|Lopker, Michael; Easlick, Juliet; Sterrett, Sarah et al. (2013) Heterogeneity in neutralization sensitivities of viruses comprising the simian immunodeficiency virus SIVsmE660 isolate and vaccine challenge stock. J Virol 87:5477-92|
|Parrish, Nicholas F; Gao, Feng; Li, Hui et al. (2013) Phenotypic properties of transmitted founder HIV-1. Proc Natl Acad Sci U S A 110:6626-33|
|Liao, Hua-Xin; Lynch, Rebecca; Zhou, Tongqing et al. (2013) Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature 496:469-76|
|Liao, Hua-Xin; Tsao, Chun-Yen; Alam, S Munir et al. (2013) Antigenicity and immunogenicity of transmitted/founder, consensus, and chronic envelope glycoproteins of human immunodeficiency virus type 1. J Virol 87:4185-201|
|Vaccari, Monica; Keele, Brandon F; Bosinger, Steven E et al. (2013) Protection afforded by an HIV vaccine candidate in macaques depends on the dose of SIVmac251 at challenge exposure. J Virol 87:3538-48|
|Kong, Rui; Li, Hui; Bibollet-Ruche, Frederic et al. (2012) Broad and potent neutralizing antibody responses elicited in natural HIV-2 infection. J Virol 86:947-60|
Showing the most recent 10 out of 11 publications