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Boily-Larouche G ., Kirwan S., Lajoie J., Kimani J., Fowke K.R.

Longitudinal analysis of mucosal immune quiescence and impact of commercial sex work in HIV Exposed Seronegative (HESN) sex workers from Nairobi, Kenya. Boily-Larouche G ., Kirwan S., Lajoie J., Kimani J., Fowke K.R. A global view of HIV infection.

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Boily-Larouche G ., Kirwan S., Lajoie J., Kimani J., Fowke K.R.

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  1. Longitudinal analysis of mucosal immune quiescence and impact of commercial sex work in HIV Exposed Seronegative (HESN) sex workers from Nairobi, Kenya Boily-Larouche G., Kirwan S., Lajoie J., Kimani J., Fowke K.R.

  2. A global view of HIV infection 34 million people living with HIV, with Sub-Saharan Africa being the most heavily affected with 72% of new infections. From: WHO/UNAIDS, 2011

  3. HIV infection • HIV preferentially establishes a productive infection in activated CD4+ T cells. • Infection of a small funder population at site of entry that is fuelled by local activation of immune cells. • Acting on the initial inflammation prevent SIV acquisition (Li et al Nature 2009)

  4. Natural correlates of protection • HIV Exposed Seronegative (HESN) • Sub-group of women from the Pumwani CSW cohort in Nairobi, Kenya remain uninfected by HIV-1 despite intense exposure • Defined as: • HIV PCR & serology neg • still active in sex work • 7 years or more of follow up remaining uninfected • HESN individuals provide a unique opportunity to study natural correlates of protection against HIV infection

  5. Immune quiescence (IQ) • HESN CSWs harboured immune quiescent phenotype • Systemic IQ • Generalized lower gene expression (McLaren JID 2010) • Lower levels of activated T cells and higher frequency of Treg in the blood (Card JID 2009) • Mucosal IQ • Low levels of chemokines (IP-10 and MIG) and cytokines (Lajoie et al. Mucosal Immunol 2012) • Higher levels of anti-inflammatory proteins (Burgener et al. J Proteome Res. 2008 )

  6. Immune activation and HIV targets • Immune activation correlates with infection Altered HIV susceptibility : IQ limits the available targets for HIV replication Card CM et al. (2012) PLoS ONE

  7. Impact of Sex Work • Sex derived antigens are powerful immune stimulants • Induced cytokines/chemokines expresionn and immune cells recruitment at the FGT (Sharkey et al. JI 2012) • Triggered peripheral allo-immune response (Peters et al. Lancet 2004) • Interindividual variability in sex-derived antigens response (activation vs tolerance) (Kingsley et al. Plos One 2009) • Sex work • Constant immune pressure • Better control of sex-derived immune activation = Protection • Sex work alters immune activation at the female genital tract, therefore cell susceptibility to HIV.

  8. Pilot Sex Break Study • Pilot Sex Break Study to determine if • Reduced sexual activity impact activation levels of the immune system • Better regulation of activation levels could contribute in protection against HIV acquisition

  9. Pilot Sex Break Study • Designed to characterize immune activation before and immediately following a break from regular sexual activity among sex workers on sabbatical. SE. Kirwan

  10. Impact of Sex Work Controls Continued active sex work Interruption in sex work 7 weeks (mean, 3-16) • Determine the impact of sex work on the level of immune systemic and mucosal activation

  11. Regulation of Immune activation in HESNs Interruption in sex work 7 weeks (mean, 3-16) New Negative (< 3 y) HIV positive HESN (>3y) 2. Determine the difference in the regulation of the levels of immune activation upon interruption in sex work and resumption of commercial sexual activity

  12. Phenotyping CD4+ T cells • CD4+ and CD8+ T cells • CD38, HLA-DR, CD69, CD107A, CCR5, CD95 CD8+ T cells Compare the proportion of expressing cells for each marker SE. Kirwan

  13. Impact of Sex Work Vaginal Mucosa : HIV+ CD4+ T cells CD8+ T cells P=0.030 P=0.016 P=0.0018

  14. Impact of Sex Work Blood : HIV+ CD8+ T cells CD4+ T cells P=0.007 P=0.053 P=0.006 P=0.079 P=0.0035 Interruption in commercial sexual activity alter the level of immune activation (CCR5, CD95)

  15. Regulation upon sex interruption Vaginal Mucosa : HESN vs New Neg CD8+ T cells HESN P=0.036 P=0.0046 New Neg Interruption in commercial sexual activity is differently regulated between HESN and New Neg

  16. Regulation following resumption to sex work * Cervical CD69+ CD4+ T cells P=0.0087 New Neg HESN HIV More targets in the vaginal tract of new negatives following resumption of sex work…

  17. Summary • Interruption in commercial sexual activity affects the levels of immune activation, especially within the HIV-positive CSWs. • Immune activation levels in genital tract of HESNs remain constant even upon return to sex work. • HESNs maintain low level of activation of CD4+ T cells in the genital tract following resumption of sex work. This would mean lesstarget cells at the site of entry.

  18. Acknowledgments UNIVERSITY OF NAIROBI UNIVERSITY OF MANITOBA • University of Winnipeg • Dr Keith Fowke and lab members • Dr Sheryl Kirwan • Dr Julie Lajoie and Jennifer Juno • Dr Frank Plummer, Dr Blake Ball & Lab Members • University of Nairobi • Dr Joshua Kimani • Dr Makobu Kimani, Charles Wachihi, Catherine Kago & other Majengo Clinic staff • Women of the Majengo Cohort • Funders

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