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

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

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)

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

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 )

Immune activation and HIV targets

Immune activation correlates with infection

Card CM et al. (2012) PLoS ONE

Altered HIV susceptibility : IQ limits the available targets for HIV replication

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.

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

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

Impact of Sex Work

ControlsContinued 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

HESN (>3y) New Negative (< 3 y)

HIV positive

Interruption in sex work 7 weeks (mean, 3-16)

2. Determine the difference in the regulation of the levels of immune activation upon interruption in sex work and resumption of commercial sexual activity

•CD4+ and CD8+ T cells•CD38, HLA-DR, CD69, CD107A, CCR5, CD95

Compare the proportion of expressing cells for each

marker

SE. Kirwan

CD4+ T cells

CD8+ T cells

Phenotyping

Impact of Sex Work

CD4+ T cells

CD8+ T cells

Vaginal Mucosa : HIV+

P=0.030 P=0.016P=0.0018

Impact of Sex Work

CD4+ T cells

CD8+ T cells

Blood : HIV+

P=0.079

P=0.053P=0.007

P=0.006

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

P=0.036

CD8+ T cells

P=0.0046HESN

Interruption in commercial sexual activity is differently regulated between HESN and New

Neg

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

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 less target cells at the site of entry.

Acknowledgments

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

UNIVERSITY OF MANITOBA

UNIVERSITY OF NAIROBI