Exploiting common targets in human fertilization and HIV infection: development of novel contraceptive microbicides

Human Reproduction Update, Vol.12, No.2 pp. 103–117, 2006 Advance Access publication September 19, 2005 doi:10.1093/humupd/dmi040 Exploiting common targets in human fertilization and HIV infection: development of novel contraceptive microbicides Gustavo F.Doncel CONRAD, Department of Obstetrics and Gynecology, The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, VA, USA To whom correspondence should be addressed at: CONRAD, Department of Obstetrics and Gynecology, The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, 601 Colley Avenue, Norfolk, VA 23507, USA. E-mail: 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 ␤-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. Key words: contraception/fertilization/HIV infection/HIV prevention/microbicides The need for contraceptive microbicides The human population is steadily increasing. We currently are 6.4 billion, and statistical projections indicate we will be about 9 billion by the year 2050 (U.S. Census Bureau, 2002). Population, however, is growing fastest in countries and regions where resource needs are the greatest. By the year 2050, 86% of the global population will live in less developed countries. Although more developed nations will not increase their population significantly, the 49 least developed countries will triple their population sizes. Accompanying high rates of population growth, poverty, malnutrition and infectious diseases are almost permanent features in many of these countries. Intricately intertwined, they compound health and social problems and interfere with their solutions. The acquired immune deficiency syndrome (AIDS) is the latest of these maladies, and it appears to thrive in the presence of overpopulation, poverty and other sexually transmitted diseases (STDs) (United Nations Population Division, 2003). Since its beginning, the AIDS epidemic has expanded relentlessly (UNAIDS, 2004). More than 30 million adults and children worldwide have died from AIDS, and about 40 million are currently infected with its causal agent, the human immunodeficiency virus (HIV). It is a reality that more than 95% of new infections (about 15 000 per day) occur in less developed countries. SubSaharan Africa remains by far the most affected region with 25.4 million people living with HIV at the end of 2004 (UNAIDS, 2004). Furthermore, women are increasingly and disproportionately affected. Globally, just under half of all people living with HIV are female, but in sub-Saharan Africa, a striking 76% of young people (aged 15–24 years) are women. © The Author 2005. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: 103 from https://academic.oup.com/humupd/article-abstract/12/2/103/700273 Downloaded by guest on 25 May 2018 G.F.Doncel It is clear that there is an urgent need for developing options that allow women to prevent or delay pregnancy and to protect themselves from STDs, especially AIDS. Although other preventative strategies are possible (e.g. behavioural changes and vaccines), development of microbicides, with and without contraceptive properties, has recently gathered momentum, owing to better science, increased funding and political pressure. For women willing to prevent pregnancy and STDs, dually active contraceptive microbicides offer convenience as well as additional safety and discretion. Single-molecule compounds also have toxicological, manufacturing and regulatory advantages. Non-contraceptive microbicides are also desperately needed, as they fit the need of a large population of women, especially in developing countries, who want to protect themselves against sexually transmitted infections while remaining fertile (Mantell et al., 2005). Because of the close interaction between microbicides with or without contraceptive activity and sperm, reproductive toxicity and teratogenicity studies are an essential part of the preclinical assessment of these compounds. So far, however, none of the compounds in clinical testing have shown significant effects on fetal development or pregnancy outcome. Fertilization and HIV infection: do they have anything in common? Anatomical context Mammalian fertilization and HIV infection possess obvious points in common. Both processes share a predominant mode of transmission (sexual), the anatomical environment in which they occur (the female reproductive tract) and the vehicles that transport sperm and HIV (semen and cervicovaginal fluids). These three commonalities offer an anatomical and logistical rationale to develop agents that may simultaneously block fertilization and HIV infection. Given that sperm and HIV travel in semen and come in contact with their targets after vaginal intercourse and ejaculation, a formulation p (...truncated)