Transcript LAMIQ - Open Medicine

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
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Sex work alters immune activation at the female genital tract, therefore
cell susceptibility to HIV.
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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