Elucidation of the bottleneck to HIV-1 and SIV transmission at mucosal surfaces of the vagina, cervix and rectum, including a precise definition ofthe eariiest virus - host interactions necessary for infection, could be instrumental in the design of effective vaccines. Our laboratories have taken significant steps toward addressing these goals by developing an experimental framework with which to identify transmitted/founder HIV-1 and SIV genomes responsible for productive infection (Keele 2008;Keele 2009;Salazar 2009) and by developing in situ methods to characterize early virus - host cell interactions underlying mucosal transmission (Li 2005;Estes 2006;Estes 2007;Estes 2008;Li 2009a). The current project combines forthe first time ivag, ir and iv transmission studies using naturally-occurring SIVsm transmitted/founder viruses Project objectives are to characterize the rectal, vaginal and cervical bottleneck to SIVsmm transmission, to identify the initial cell types productively infected by transmitted/founder SIVsmm, and to identify early innate Immune responses that act to constrain or facilitate productive viral Infection. By examining the transmissibllity of molecularly-cloned transmitted/founder viruses from SIVsmm strains FTq, D215 and SL92b, along with SIVmac239 and infectious monkey plasmas containing complex SIVsmm quasispecies, we will test the following hypothesis: Distinct barriers to SIVsmm transmission exist at mucosal interfaces of the vagina, cervix and rectum. These barriers are both passive (sieving) and active in nature, the latter selecting for viruses with particular cellular tropism and replication properties necessary for transmission and productive infection.
Specific Aims of the project are: (1) To quantify and characterize phylogenetically the bottleneck to rectal versus cervicovaginal versus intravenous transmission by naturally-occurring SIVsmm

Public Health Relevance

It is widely believed that a sterilizing HIV or SIV vaccine will either need to prevent virus transmission before the first cell is infected, or it will need to interrupt the eariiest sequence of infection events. This project will characterize the mucosal bottleneck to virus transmission and eariy virus-host interactions required for virus transmission and the establishment of productive clinical infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI088564-05
Application #
8497587
Study Section
Special Emphasis Panel (ZAI1-RB-A)
Project Start
2013-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$657,126
Indirect Cost
$125,891
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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