The development of an effective AIDS vaccine remains one of the highest priorities in HIV research. Studies of HIV pathogenesis, vaccine design and antiretroviral treatments require an appropriate animal model. However, the existing SIV/macaque model has major limitations since (i) prototypic SIVmac strains are too pathogenic, (ii) do not represent mucosally transmitted viruses, and (iii) have been extensively passaged in vitro and in vivo. We have recently identified a large set of new SIVsmm strains which mirror HIV-1 group M viruses in their genetic diversity. Moreover, preliminary in vivo results show that infection of RMs with these SIVsmm strains more closely reproduces the natural history of HIV-1 in humans. Within this HIVRAD consortium, we thus propose to use these new SIVsmm strains to generate new (molecularly cloned) challenge viruses for AIDS vaccine and pathogenesis studies. Project 1 will use a dose-escalation strategy to infect 21 Indian rhesus macaques (RMs) with genetically diverse SIVsmm strains using intravenous (iv), intrarectal (ir) and intravaginal (ivag) routes. Project 2 will then employ single genome amplification (SGA) techniques to infer, and subsequently clone, transmitted/founder (T/F) virus(es) from all of these animals. Following detailed in vitro characterization, a subset of clones will be selected for in vivo competition (n=18) and pathogenesis (n=8) studies which will be performed by Project 1.
Specific Aims i nclude: 1. To generate high titer plasma stocks of genetically divergent SIVsmm strains without in vitro adaptation for subsequent mucosal and intravenous transmission studies. 2. To infect RMs by intravenous, intrarectal and intravaginal routes with physiologically relevant doses of genetically divergent SIVsmm strains to allow for the identification of transmitted founder (T/F) viruses: 3.;To identify SIVsmm clones with, preferential mucosal transmissibility and replication fitness by conducting an in vivo competition experiment. 4. To characterize the selected SIVsmm clones for in vivo replication kinetics, pathogenicity and suitability as vaccine challenge stocks. We expect these studies to generate new infectious molecular clones of SIVs with biological properties that more faithfully recapitulate the transmission, pathogenic and diversity of HIV-1 in humans.
This project will generate new viral stocks and virological reagents critically needed to elucidate the molecular and cellular events that are responsible for HIV/SIV transmission across rectal and vaginal/cervical mucosa and thus eliminate a major roadblock to AIDS 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