Transgender People: Immunity, Prevention, and Treatment of HIV and STIs (R21 Clinical Trial Not Allowed)

Section I. Funding Opportunity Description Purpose There are approximately 25 million transgender people worldwide. Globally, an estimated 19% of transgender women are living with HIV. In the U.S transgender people represent 0.6% of the population with 0.7% of these individuals between the ages of 13 to 17. Cumulative data from transgender women (11,066 individuals in 39 studies in 15 countries) has clearly shown that the risk of HIV infection is ~49-fold higher than other adult populations. In contrast, there are minimal data available on the impact of HIV in transgender men and the role/impact of STIs other than HIV in transgender populations. Behavioral and social factors, such as poverty, violence, food and housing insecurity, and social stigma have been identified as contributors to the high rate of HIV infection in transgender women and possibly men. Significant research resources have been devoted to understanding the impact of these factors on transgender people. However, there has been limited research into the biological and immunological factors that might contribute to health disparities that transgender people may encounter, such as increased HIV and STI susceptibility and infection. This announcement is a continued focus on the unique constellation of biophysical and immunological changes that might contribute to the increased susceptibility of transgender people to HIV and STIs, such as Neisseria gonorrhea, Chlamydia trachomatis, and Treponema pallidum, and to understand the impact of gender affirmation surgeries on the immune system, susceptibility to infection and the efficacy and safety of treatment and prevention strategies used to treat and prevent HIV and STI infections. Research Objectives The FOA will support short duration, high-risk and innovative, hypothesis-generating research focused on describing the systemic and mucosal impact of the drugs, hormones and surgical interventions used for gender reassignment and their impact on susceptibility to HIV and other sexually transmitted infections (STI) in transgender people. The biophysical process of gender reassignment can be a complicated process involving the use of drugs and hormones to suppress and/or support acquisition and maintenance of primary and secondary sex characteristics. The pharmacological manipulations used to achieve the desired gender identity may range from halting puberty in adolescent boys and girls to chemical/surgical menopause in adults with or without surgical creation of neo-organs (vagina or penis) corresponding to the desired gender identity. Maintenance of gender identity requires continued use of hormones and drugs to suppress and maintain sexual characteristics, in addition to additional cosmetic surgeries and injection of substances, e.g., collagen, silicon, etc., to create/strengthen the desired gender identity image. The pharmacological and surgical regimens used may result in unique biological micro-and macroenvironmental changes that impact susceptibility to infection by modifying innate and cellular immunity, altering mucosal and organismal biomes (e.g., microbiome, virome, fungiome, etc.), creating new sites for HIV and STI entry, inducing acute and/or chronic inflammation, stimulating wound repair and foreign body responses, and modifying metabolic pathways that may favor infection by HIV and bacterial and viral STIs. Gender reassignment/maintenance regimens can also impact the pharmacokinetics (PK) and pharmacodynamics (PD) of the drugs and antivirals used to treat and/or prevent HIV and STIs. Thus, addressing this research gap is critical to understanding health disparities in transgender people and for developing effective strategies to prevent and treat HIV and STI acquisition and infection. These research efforts are intended to provide the underpinnings for future investigator-initiated applications Research Areas of Interest Applicants are encouraged to consider specifying milestones and timelines for their proposed research. Research may be focused on one or more of the following topics as it relates to transgender people and susceptibility, infection, acquisition and treatment of HIV and other STIs. Immunological and biome characterization of the neo-vagina and neo-penis and the impact of post-surgical femininization and masculinization processes, respectively, on the immune system and susceptibility to HIV and STI infections in these neo-organs. The impact of exogenous hormone usage (estrogens and/or progestins and/or testosterone) and/or non-hormonal drugs to suppress or enhance the acquisition and maintenance of desired gender characteristics on the immune response and susceptibility to HIV and other STIs infection. The impact of feminization and masculinization regimens on the rectal and GI mucosal and their role in HIV and STI susceptibility, infection and acquisition in transgender people. The impact of chemical and/or surgical menopause or delay of the onset of puberty in preparation for gender reassignment on the immune response, proteome and biome of transgender people. Characterization and elucidation of the role of the new micro- and macro-environments created by the surgical processes involved in creating neo-organs that might influence susceptibility to HIV and STI infection. Characteristics and function of the microbiome in the neo-vagina and neo-penis and the role of the source of tissue used to create the neo-vagina and -penis in determining the microbiome. "Omic" studies (e.g., metabolomic, proteomic, transcriptomic, etc.) and the use of systems biology tools to characterize the impact of the feminization and masculinization processes on remaining genital tract, GI tract and neo-organs. PKs and PDs of drugs used to prevent and treat HIV and STI infection in transgender people. Development of new in vitro, ex vivo and animal models to study the cellular, immunological, PK, and PD impact of gender reassignment and maintenance. The impact of hormone treatment on induction and evaluation of systemic and mucosal immune responses to HIV vaccines, transfused bNAbs or long acting antiretrovirals. The following types of applications will NOT be supported through this FOA: Studies designed to assess the efficacy of femininization and/or masculinization regimens or development of new drugs or surgical processes to achieve gender reassignment. Behavioral and/or social studies or interventions focused on understanding the role of social and behavioral factors in susceptibility to HIV and STIs in transgender people. Development of new drugs or drug delivery systems for transgender people to prevent HIV or STI infection. See Section VIII. Other Information for award authorities and regulations.