Exploiting common targets in human fertilization and HIV infection: development of novel contraceptive microbicides.
The continued high rates of unintended pregnancies and the unrelentless expansion of the acquired immune deficiency syndrome (AIDS) epidemic, especially in less developed countries, warrant the development of novel strategies to help individuals avoid these risks. Dually active compounds displaying contraceptive and microbicidal anti-human immunodeficiency virus (anti-HIV) properties constitute one such strategy. Sharing the same anatomical and functional context, sperm fertilization and genital infection by HIV offer an opportunity for simultaneous intervention. Some of the molecules and mechanisms used by sperm to fertilize the oocyte are similar, if not identical, to those used by HIV while infecting host cells. An example of common structures is the lipid membrane surrounding the spermatozoon and the HIV core. Disruption of its architecture by surface-active compounds exerts both spermicidal and virucidal activity. A more specific alteration of lipid rafts [membrane microdomains enriched in cholesterol and glycosylphosphatidylinositol (GPI)-anchored proteins] by beta-cyclodextrins also results in similar effects. During fertilization and infection, both sperm and HIV interact with their target cell receptors through chemical charges, hydrophobic forces and carbohydrate recognition. Anionic polymers such as cellulose sulphate and polystyrene sulphonate (PSS) inhibit sperm and HIV cell binding. Because some of the molecules involved in this interaction, e.g. heparin sulphate proteoglycan, are also used by other pathogens to infect their target tissues, polyanions exert broad antimicrobial activity as well. During fertilization and infection, sperm and HIV, as well as other microbes, use signal transduction molecules and mechanisms such as adenyl cyclase/cyclic adenosine monophosphate (cAMP)-dependent kinase, calcium and tyrosine phosphorylation, whose inhibition has been shown to impair sperm function and HIV replication. These commonalities at the level of sperm and HIV structure, cell binding and fusion processes, and signalling pathways therefore provide the biological framework to develop bifunctional inhibitors with both antimicrobial and contraceptive properties.
Doncel
Gustavo F
GF
CONRAD, Department of Obstetrics and Gynecology, The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, 23507, USA. doncelgf@evms.edu
D019380:Anti-HIV Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003267:Contraception / Q000379:methods*; D005260:Female; D005306:Fertilization / Q000187:drug effects / Q000502:physiology*; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D009092:Mucous Membrane / Q000382:microbiology / Q000821:virology; D011247:Pregnancy; D015398:Signal Transduction; D013089:Spermatocidal Agents / Q000494:pharmacology*; D013094:Spermatozoa / Q000187:drug effects / Q000502:physiology* / Q000821:virology
D019380:Anti-HIV Agents; D013089:Spermatocidal Agents