HIV in the acidic cervicovaginal fluids of infected women is likely coated by anti-Env antibodies. Since HIV is sexually transmitted, these antibodies do not always prevent infection in the recipient partner and therefore may be of insufficient quantity or quality to neutralize virus in vivo. But could the antibodies that coat HI in genital tract secretions facilitate mucosal transmission? This question will be addressed with a rhesus macaque model of penile SIV exposure. We will test the hypothesis that antibody facilitates lentivirus transmission across genital tract mucosa. The hypothesis is based on our finding of marked enhancement of transcytosis of HIV immune complexes due to pH-dependent engagement of epithelial cell Fc neonatal receptors (FcRn). In addition, transmitted/founder (T/F) strains of HIV tend to bind better to antibodies and to be more susceptible to neutralization than are strains isolated late in infection, raising the possibility that antibody selects strains or successful transmission across mucosal surfaces. We will accomplish the following specific aims: 1) Determine the impact of pH and low concentrations of antibody on transmission efficiency following penile exposure of rhesus macaques to SIV. An established penile exposure model will be modified to test the effects of anti-Env antibody, at concentrations similar to those found in female genital tract secretions, on penile SIV transmission;and 2) Delineate the role of antibody in selecting T/F strains of SIV following penile exposure. The number of T/F strains and their env sequences, from animals infected with antibody-coated and with uncoated virus, will be compared. In addition, pseudoviruses will be constructed to determine if T/F Env pseudoviruses can be phenotypically distinguished from non-T/F Env pseudoviruses in antibody/pH-dependent transcytosis assays. We believe this research will define a completely novel mechanism of sexual transmission of lentiviruses, generating critical data on early events in infection that will shift current paradigms and inform vaccine development. Specifically, if immune-complexed virus behaves differently than naked virus with respect to mucosal transmission across male genital tissue, current animal challenge models, which, to our knowledge, exclusively utilize naked virus, would require re-evaluation. Additionally, antibody responses generated by vaccination would need to successfully compete with donor antibody bound to virus and be of sufficient quantity and quality to avoid the potential of facilitating transmission. Finally, this research may suggest novel prevention strategies targeting FcRn-mediated transcytosis.
This research focuses on sexual transmission of HIV, a problem of huge public health concern. We propose a novel mechanism by which transmission might occur, and our investigations might lead to new strategies to prevent infection.
|Hicar, Mark D; Chen, Xuemin; Kalams, Spyros A et al. (2016) Low frequency of broadly neutralizing HIV antibodies during chronic infection even in quaternary epitope targeting antibodies containing large numbers of somatic mutations. Mol Immunol 70:94-103|
|Gupta, Sandeep; Pegu, Poonam; Venzon, David J et al. (2015) Enhanced in vitro transcytosis of simian immunodeficiency virus mediated by vaccine-induced antibody predicts transmitted/founder strain number after rectal challenge. J Infect Dis 211:45-52|
|Forthal, Donald N (2014) Functions of Antibodies. Microbiol Spectr 2:1-17|
|Forthal, Donald N (2014) Functions of Antibodies. Microbiol Spectr 2:AID-0019-2014|
|Gorlani, Andrea; Forthal, Donald N (2013) Antibody-dependent enhancement and the risk of HIV infection. Curr HIV Res 11:421-6|
|Gupta, Sandeep; Gach, Johannes S; Becerra, Juan C et al. (2013) The Neonatal Fc receptor (FcRn) enhances human immunodeficiency virus type 1 (HIV-1) transcytosis across epithelial cells. PLoS Pathog 9:e1003776|