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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. S 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 HIV infection S HIV preferentially establishes a productive infection in activated CD4+ T cells. S Infection of a small funder population at site of entry that is fuelled by local activation of immune cells. S Acting on the initial inflammation prevent SIV acquisition (Li et al Nature 2009) Natural correlates of protection S HIV Exposed Seronegative (HESN) S 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 S HESN individuals provide a unique opportunity to study natural correlates of protection against HIV infection Immune quiescence (IQ) S HESN CSWs harboured immune quiescent phenotype S Systemic IQ S Generalized lower gene expression (McLaren JID 2010) S Lower levels of activated T cells and higher frequency of Treg in the blood (Card JID 2009) S Mucosal IQ S Low levels of chemokines (IP-10 and MIG) and cytokines (Lajoie et al. Mucosal Immunol 2012) S Higher levels of anti-inflammatory proteins (Burgener et al. J Proteome Res. 2008 ) Immune activation and HIV targets S Immune activation correlates with infection Altered HIV susceptibility : IQ limits the available targets for HIV replication Card CM et al. (2012) PLoS ONE Impact of Sex Work S Sex work alters immune activation at the female genital tract, therefore cell susceptibility to HIV. S Sex derived antigens are powerful immune stimulants S Induced cytokines/chemokines expresionn and immune cells recruitment at the FGT (Sharkey et al. JI 2012) S Triggered peripheral allo-immune response (Peters et al. Lancet 2004) S Interindividual variability in sex-derived antigens response (activation vs tolerance) (Kingsley et al. Plos One 2009) S Sex work S Constant immune pressure S Better control of sex-derived immune activation = Protection Pilot Sex Break Study S Pilot Sex Break Study to determine if S Reduced sexual activity impact activation levels of the immune system S Better regulation of activation levels could contribute in protection against HIV acquisition Pilot Sex Break Study S Designed to characterize immune activation before and immediately following a break from regular sexual activity among sex workers on sabbatical. SE. Kirwan Impact of Sex Work Controls Continued active sex work Interruption in sex work 7 weeks (mean, 3-16) 1. Determine the impact of sex work on the level of immune systemic and mucosal activation Regulation of Immune activation in HESNs Interruption in sex work 7 weeks (mean, 3-16) HESN (>3y) New Negative (< 3 y) HIV positive 2. Determine the difference in the regulation of the levels of immune activation upon interruption in sex work and resumption of commercial sexual activity Phenotyping •CD4+ and CD8+ T cells •CD38, HLA-DR, CD69, CD107A, CCR5, CD95 CD4+ T cells CD8+ T cells Compare the proportion of expressing cells for each marker SE. Kirwan Impact of Sex Work Vaginal Mucosa : HIV+ CD4+ T cells P=0.030 CD8+ T cells P=0.016 P=0.0018 Impact of Sex Work Blood : HIV+ CD8+ T cells CD4+ T cells P=0.053 P=0.007 P=0.006 P=0.079 P=0.0035 Interruption in commercial sexual activity alter the level of immune activation (CCR5, CD95) 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 Regulation following resumption to sex work * Cervical CD69+ CD4+ T cells P=0.0087 HESN New Neg HIV More targets in the vaginal tract of new negatives following resumption of sex work… Summary S Interruption in commercial sexual activity affects the levels of immune activation, especially within the HIV-positive CSWs. S Immune activation levels in genital tract of HESNs remain constant even upon return to sex work. S HESNs maintain low level of activation of CD4+ T cells in the genital tract following resumption of sex work. This would mean less target cells at the site of entry. Acknowledgments UNIVERSITY OF NAIROBI UNIVERSITY OF MANITOBA S S S University of Winnipeg S Dr Keith Fowke and lab members S Dr Sheryl Kirwan S Dr Julie Lajoie and Jennifer Juno Dr Frank Plummer, Dr Blake Ball & Lab Members University of Nairobi S Dr Joshua Kimani S Dr Makobu Kimani, Charles Wachihi, Catherine Kago & other Majengo Clinic staff S Women of the Majengo Cohort S Funders