Elucidation of the bottleneck to HIV-1 and SIV transmission at mucosal surfaces of the vagina, cervix and rectum, including a precise definition of the earliest 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 for the 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 earliest sequence of infection events. This project will characterize the mucosal bottleneck to virus transmission and early virus-host interactions required for virus transmission and the establishment of productive clinical infection.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
United States
Zip Code
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