One of the most important knowledge gaps in HIV/SIV vaccine research relates to the biological properties of viruses that are responsible for mucosal transmission. Within this HIVRAD consortium, this project will address this priority area by taking advantage of our laboratory's recent discovery of a novel strategy for identifying mucosally transmitted HIV-1 and SIV viral genomes (Salazar et al., J Virol, 2008; Keele, PNAS, 2008;Salazar, J Exp Med, 2009;Keele, J Exp Med, 2009). This strategy, which is based on single genome amplification, sequencing and analysis of plasma viral RNA within the context of a model of random virus evolution, identifies those viruses that are actually responsible for transmission and productive infection. This innovation, in turn, makes possible for the first time the molecular cloning and biological characterization of such transmitted/founder virus genomes. In this project, we propose to extend this enabling technology to the SIV-macaque infection model to test the following hypothesis: Molecular clones of transmitted/founder SIVs will reveal the particular properties of cell tropism, receptor and co-receptor usage, and neutralization phenotype that are necessary and sufficient for successful transmission via intrarectal, intravaginal and intravenous infection routes.
Specific aims i nclude: 1. To identify and enumerate transmitted/founder viruses in Indian rhesus macaques following intrarectal, intravaginal and intravenous infection with new genetically diverse SIVsmm strains. To moleculariy clone full-length genomes of transmitted/founder viruses responsible for productive infection by intrarectal, intravaginal and intravenous routes. To determine the in vitro biological properties of molecular clone-derived transmitted/founder viruses. To prepare stocks of transmitted/founder viruses for in vivo testing in Indian rhesus macaques. Results from these studies will shed new light on the molecular mechanisms underiying mucosal HIV/SIV transmission, identify new targets for vaccine-elicited immune responses, and generate a much needed set of new genetically-diverse SIV challenge strains for transmission, pathogenesis and vaccine research.
Using the transmitted/founder virus clones generated in this project we will, for the first time, be able to address whether viruses that are transmitted across mucosal surfaces are phenotypically different from viruses that are transmitted intravenously. This information will eliminate a major roadblock to our understanding ofthe eariiest HIV-1 infection events and is thus critically important for vaccine development.
|Li, Hui; Wang, Shuyi; Kong, Rui et al. (2016) Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques. Proc Natl Acad Sci U S A 113:E3413-22|
|Mason, Rosemarie D; Welles, Hugh C; Adams, Cameron et al. (2016) Targeted Isolation of Antibodies Directed against Major Sites of SIV Env Vulnerability. PLoS Pathog 12:e1005537|
|Raehtz, Kevin; Pandrea, Ivona; Apetrei, Cristian (2016) The well-tempered SIV infection: Pathogenesis of SIV infection in natural hosts in the wild, with emphasis on virus transmission and early events post-infection that may contribute to protection from disease progression. Infect Genet Evol :|
|Pandrea, Ivona; Xu, Cuiling; Stock, Jennifer L et al. (2016) Antibiotic and Antiinflammatory Therapy Transiently Reduces Inflammation and Hypercoagulation in Acutely SIV-Infected Pigtailed Macaques. PLoS Pathog 12:e1005384|
|Bailey, Adam L; Lauck, Michael; Sibley, Samuel D et al. (2015) Zoonotic Potential of Simian Arteriviruses. J Virol 90:630-5|
|Policicchio, Benjamin B; Pandrea, Ivona; Apetrei, Cristian (2015) Population Bottlenecks and Pathogen Extinction: "Make This Everyone's Mission to Mars, Including Yours". J Virol 89:8104-6|
|Ma, Dongzhu; Xu, Cuiling; Cillo, Anthony R et al. (2015) Simian Immunodeficiency Virus SIVsab Infection of Rhesus Macaques as a Model of Complete Immunological Suppression with Persistent Reservoirs of Replication-Competent Virus: Implications for Cure Research. J Virol 89:6155-60|
|Barbian, Hannah J; Decker, Julie M; Bibollet-Ruche, Frederic et al. (2015) Neutralization properties of simian immunodeficiency viruses infecting chimpanzees and gorillas. MBio 6:|
|Langer, Simon M; Hopfensperger, Kristina; Iyer, Shilpa S et al. (2015) A Naturally Occurring rev1-vpu Fusion Gene Does Not Confer a Fitness Advantage to HIV-1. PLoS One 10:e0142118|
|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|
Showing the most recent 10 out of 21 publications