In 2007, the World Health Organization (WHO) recommended male circumcision as an effective means of reducing heterosexual HIV transmission in HIV endemic regions. This led multiple African countries to establish circumcision clinics offering free surgical procedure to adult men. The effect of circumcision on HIV transmission has fuelled interest in the scientific community studying immune correlates of susceptibility to HIV infection. In line with this, the newly established circumcision programs provided a source of samples required to directly assess the correlates of susceptibility in preputial tissue. An article recently published by Dr. Rupert Kaul’s research team in Mucosal Immunology investigated the differences in the foreskin immunology between HIV-exposed but seronegative (HESN) men and their healthy HIV-unexposed counterparts. It is one of four papers that Jessica Prodger published while completing her PhD (Institute of Medical Science, University of Toronto, 2014) that aim to better characterize how preputial tissue may make men more susceptible or resistant to HIV.

Circumcision and HIV
Male circumcision as a means of protecting against HIV acquisition was for the first time proposed in 1986 by Dr Valiere Alcena at Einstein College of Medicine in a letter to the editor of the New York State Journal of Medicine. SubsequentlHIV Virionsy multiple groups studied the relationship between circumcision and HIV transmission, until in 2005-2007 three randomized clinical trials were conducted in South Africa, Kenya and Uganda showing that male circumcision reduced the risk of female-to-male HIV transmission by up to 60%, thus underscoring the role of foreskin as a major portal of entry for the virus.

While the majority of individuals repeatedly exposed to HIV through sexual activity ultimately become infected, some people are capable of showing resistance to the virus and remain HIV seronegative despite being in a sexual relationship with infected partners. The reasons for such persistent seronegativity could be multiple, including the genetic background and environmental factors, which in combination create an immunological milieu protective against HIV. To explore what makes some men less susceptible to HIV than others, Dr. Kaul’s research team collaborated with a circumcision trial site in Rakai, Uganda, where they analyzed surgically removed foreskins from HIV exposed but seronegative (HESN) men and compared them with the foreskins from HIV unexposed healthy men.

Sources of Foreskin
Prodger and co-authors undertook a formidable task of collecting and analyzing samples from 110 men who chose to undergo elective circumcision at the Rakai Health Sciences Program. Only samples from HIV-uninfected men were used. Twenty of the 77 HIV-negative men were in a stable relationship with an HIV-infected woman who had detectable plasma viral load. Despite having been exposed through their partners to HIV for an average of 5 years, these men maintained HIV-seronegative status and were classified as “HESN”. The remaining 57 HIV-negative men were in a monogamous relationship with an HIV-uninfected female partner, and reported no extramarital relationships. As opposed to HESN men, these individuals had not been under the selective pressure of prolonged HIV exposure. After circumcision, foreskin samples were used to extract cells for flow cytometric analyses, while preputial swabs were examined to assess levels of soluble innate immune factors and the ability of foreskin-secreted immunoglobulin A (IgA) to inhibit HIV infection.

What Makes HESN Foreskin Different?
Analysis of the data revealed intriguing differences between the immunological milieu of foreskin from HESN and HIV-unexposed men. In particular, HESN foreskin was characterized by increased levels of alpha-defensins, also known as human neutrophil peptides (HNPs)- small cysteine-rich molecules that exhibit potent microbicidal activity and play important roles in innate immune responses on mucosal surfaces, including their known ability to block HIV replication.

Another interesting finding pertained to the preputial IgA: in 50% of the HESN men it was capable of neutralizing HIV, while only 11% of healthy controls exhibited similar activity.  Paradoxically, HESN foreskin had a higher density of CD4+ T lymphocytes, cells that are specifically targeted by HIV, compared to HIV-unexposed controls. However, a closer examination of T cell subpopulations revealed low percentages of Th17 phenotype and TNF-alpha producing cells in HESN foreskins. Given that Th17 cells are preferentially infected by HIV in vitro, and that TNF-alpha plays a role in attracting CD4+ T cells and activating dendritic cells, another cell type that can be infected by the virus, these findings may explain why HESN men are capable of successfully resisting the HIV infection and maintain a long term HIV seronegative status.

The Mucosal Immunology article is a sequel to three other papers by Prodger and co-authors that explored the different aspects of foreskin immunology, such as the functional profiles of T cells and impact of herpes simplex virus infection on T cell phenotype and function. This work adds a valuable piece to our growing knowledge about the immune mechanisms that determine the extent to which the male genital tract is susceptible to HIV invasion. Further investigation of these mechanisms, an objective of high priority in Dr. Kaul’s research program, will undoubtedly facilitate the ongoing search for effective microbicidals and vaccines against HIV.

Thanks to Dr. Jessica Prodger and Dr. Rupert Kaul for the valuable discussion and comments on the article.

Article Citation

Prodger JL, Hirbod T, Kigozi G, Nalugoda F, Reynolds SJ, Galiwango R, et al. Immune correlates of HIV exposure without infection in foreskins of men from Rakai, Uganda. Mucosal Immunol 2014,7:634-644.

References

  1. Clearinghouse on male circumcision for HIV prevention. http://www.malecircumcision.org/index.html, accessed on 02.09.2014
  2. Moses S., et al. Geographical patterns of male circumcision practices in Africa: association with HIV seroprevalence. International Journal of Epidemiology 1990;19:693-697.
  3. Garenne M. Male circumcision and HIV control in Africa. PLoS Med 2006;3(1):e78.
  4. Gray RH, et al. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet 2007,369:657-666.
  5. Prodger JL, et al. Impact of asymptomatic Herpes simplex virus-2 infection on T cell phenotype and function in the foreskin. AIDS 2012,26:1319-1322.
  6. Prodger JL, et al. Foreskin T-cell subsets differ substantially from blood with respect to HIV co-receptor expression, inflammatory profile, and memory status. Mucosal Immunol 2012,5:121-128.
  7. Prodger JL, et al. HIV Infection in Uncircumcised Men Is Associated With Altered CD8 T-cell Function But Normal CD4 T-cell Numbers in the Foreskin. J Infect Dis 2014,209:1185-1194.
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Sergey Yegorov

Sergey received his BSc in Biology from Acadia University (NS) and MSc in Bioscience and Technology from the University of Winnipeg. He is currently a PhD student in the Department of Immunology at the University of Toronto.

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