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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI116252-01A1
Application #
8922912
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Turpin, Jim A
Project Start
2015-07-01
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Urology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
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Roan, Nadia R; Sandi-Monroy, Nathallie; Kohgadai, Nargis et al. (2017) Semen amyloids participate in spermatozoa selection and clearance. Elife 6:
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