The continuing spread of HIV/AIDS in people is predominantly fueled by sexual exposure to HIV-contaminated semen/seminal plasma (SP). SP harbors HIV infectivity enhancing factors that include at least two major classes of naturally occurring amyloid fibrils that promote virion attachment to cellular targets. SP also harbors a variety of pro- inflammatory factors that can indirectly facilitate HIV transmission by promoting the production of cytokines/chemokines that recruit permissive cells, enhance the translocation of HIV across the genital epithelium, and activate HIV gene transcription. These direct and indirect HIV- enhancing effects of SP could help explain the general lack of success in developing a highly efficacious HIV microbicide. To identify inhibitors of SP's HIV-enhancing activity, we conducted a small molecule screen for disassemblers of HIV-enhancing SP amyloids. We identified four hits, one of which was gallic acid (GA), a naturally-occurring compound present in grape seeds that has previously been reported to inhibit fibril formation by amyloidogenic peptides associated with neurological diseases. We confirmed that GA inhibits the ability of both SP and SP amyloids to enhance HIV infection. Interestingly, GA has previously been reported to harbor anti-inflammatory properties, including the ability to inhibit NF-kB signaling. Together, these observations suggest that GA may inhibit SP-mediated enhancement of HIV infection by dually targeting the amyloids and the pro-inflammatory properties of SP. In this project, we characterize the conditions under which GA and the other 3 compound hits inhibit the activity of SP amyloids and the mechanisms by which this occurs (Aim 1), and determine whether GA inhibits SP-induced genital inflammation that can facilitate transmission (Aim 2). These studies will reveal whether GA and other chemical disassemblers would be a promising compound to develop further as a component of an HIV microbicide, and provide insights into the multiple mechanisms by which SP can enhance HIV transmission.

Public Health Relevance

New approaches to limit the sexual spread of Human Immunodeficiency Virus-1 (HIV-1) are urgently needed. We propose a novel approach to prevent the spread of HIV-1 by inhibiting the activity of semen amyloids that markedly enhance HIV-1 infectivity through the use of a naturally-occurring compound with anti-amyloid and anti-inflammatory properties. Our intention is to eventually combine this inhibitor with conventional microbicides directly targeting the HIV-1 virus, to develop a novel class of 'combination microbicides.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Turpin, Jim A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Röcker, Annika; Roan, Nadia R; Yadav, Jay Kant et al. (2018) Structure, function and antagonism of semen amyloids. Chem Commun (Camb) 54:7557-7569
Martin, Jeremy W; Chen, Joseph C; Neidleman, Jason et al. (2018) Potent and rapid activation of tropomyosin-receptor kinase A in endometrial stromal fibroblasts by seminal plasma. Biol Reprod 99:336-348
Roan, Nadia R; Sandi-Monroy, Nathallie; Kohgadai, Nargis et al. (2017) Semen amyloids participate in spermatozoa selection and clearance. Elife 6:
Neidleman, Jason A; Chen, Joseph C; Kohgadai, Nargis et al. (2017) Mucosal stromal fibroblasts markedly enhance HIV infection of CD4+ T cells. PLoS Pathog 13:e1006163
Bergman, P; Roan, N R; Römling, U et al. (2016) Amyloid formation: functional friend or fearful foe? J Intern Med 280:139-52
Roan, Nadia R; Jakobsen, Martin R (2016) Friend or Foe: Innate Sensing of HIV in the Female Reproductive Tract. Curr HIV/AIDS Rep 13:53-63
LoRicco, Josephine G; Xu, Changmingzi Sherry; Neidleman, Jason et al. (2016) Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection. J Biol Chem 291:14045-55