(Provided by the Applicant): To develop a functional microbicide it is critical to know how it will interact within HIV in the context of the female genital tract. This is a critical issue as previous clinical trials have indicated that microbicides do not function as expected in the presence of semen. Likewise, other factors, such as cervical/vaginal mucus, might also modulate microbicide function. To date, little is known about how HIV interacts with these fluids and how the interaction of these fluids changes the local environment. Even less is known about how microbicides interact with HIV within this milieu. For example, the vehicle delivering the microbicide might interact with the biological fluids of sexual transmission to either increase or inhibit HIV acquisition or microbicide potency. The Hope laboratory has recently developed methods that allow the transport of HIV with cervical and cervical/vaginal mucus to be analyzed and quantified. These studies have revealed that mucus can perturb HIV transport and is pH sensitive. At acidic pH, as is found in the lactobacilli influenced environment of the vaginal vault, HIV transport is greatly reduced. At neutral pH, such as when semen is introduced into the system, HIV transport is reduced 10-15 fold relative to what is observed in media (water). Additionally, we have found, but not yet published, that virus-binding antibodies can further reduce transport in neutral pH cervical mucus. These antibodies do not need to be neutralizing as any antibody binding to the virus can decrease virus transport. Semen also contains mucins and other components that have the potential to alter HIV transport as we have observed in cervical mucus. How HIV is transported within semen and how this changes when mixed with mucus or microbicides is not defined. How this process influences HIV transport and interaction with mucosal barriers is not understood. In the first phase (R21) of this proposal we will define how HIV is transported in semen alone and mixed with mucus and/or microbicide vehicles such as carbopol gel and hydroxy ethyl cellulose (HEC). In the second phase (R33) of this proposal we will extend our studies into the environment of the rhesus macaque female genital tract to determine how biological fluids and microbicide vehicles alter the way that virus interacts with the mucosal barriers of this environment and how these changes can increase or decrease SIV acquisition. These studies will lead to a better understanding of how virus interacts with biological fluids and how these interactions might alter microbicide efficacy.
To design and implement interventions that inhibit HIV acquisition it is critical that we have a better understanding of how HIV interacts with the bodily fluids that are the vehicles of transmission. The studies proposed in this application will determine how HIV is transported in bodily fluids and how this transport can be altered by the presence of antibodies, microbicides, and other factors. This increased understanding will facilitate the development of a microbicide that decreased the spread of HIV.
|Fahrbach, Kelly M; Malykhina, Olga; Stieh, Daniel J et al. (2013) Differential binding of IgG and IgA to mucus of the female reproductive tract. PLoS One 8:e76176|
|Shukair, S A; Allen, S A; Cianci, G C et al. (2013) Human cervicovaginal mucus contains an activity that hinders HIV-1 movement. Mucosal Immunol 6:427-34|