1

Highly HIV exposed seronegative (HESN) sex workers from Nairobi, Kenya have altered innate mucosal immune

responses at the level of the female genital tract

AIDS 2012

T. Blake BallNational Laboratory for HIV Immunology, Public Health Agency Canada

Immunology and Medical Microbiology University of of Manitoba

Resistance to HIV-1 Infection

7 years follow, HIV-1 serology and PCR negative, Active in sex work.

10% of highly exposed sex workers resistant to HIV-1.

Years of Followup

20181614121086420

Sur

viva

l Pro

babi

lity

1.0

.8

.6

.4

.2

0.0

Decline in HIV-1 Incidence with follow up in the Pumwani Cohort.

Adapted from Fowke et al Lancet 1996

FGT is the source of majority of HIV transmission Worldwide

Already remarkably able to block HIV infection as only a minority of virus can breakthru mucosal bottleneck

Many Innate factors identified that are thought to inhibit infection (SLPI/RANTES/etc)

Unbiased system biology approaches provide insight as to what may be unique in FGT of HIV-R SW’s Years of Followup

20181614121086420

Sur

viva

l Pro

babi

lity

1.0

.8

.6

.4

.2

0.0

Decline in HIV-1 Incidence with follow up in the Pumwani Cohort.

Adapted from Fowke et al Lancet 1996

N=120

N=76

Cervical lavage

Specific antiproteases are overexpressed in genital secretions of HIV-R women

Overexpressed Underexpressed

Gene ontology of 41 (of 400+ identified) differentially expressed proteins in the cervical mucosa of HIV-1-resistant women as identified by mass spectrometry.

Cervical lavage

Specific antiproteases are overexpressed in genital secretions of HIV-R women

Overexpressed Underexpressed

Gene ontology of 41 (of 400+ identified) differentially expressed proteins in the cervical mucosa of HIV-1-resistant women as identified by mass spectrometry.

Cervical lavage

Apo A1

P=0.006

P=0.003

P=0.02P=0.19

Serpin A1 Serpin A3 Cystatin A

Serpin B3

P=0.02

P=0.0002

Specific antiproteases are overexpressed in genital secretions of HIV-R women

HIV-resistant women do not have elevated levels of pro-inflammatory cytokines in their cervical mucosa

•Specific antiproteases with known anti-inflamatory and anti-HIV activities are overexpressed in the absence of an inflammatory cytokine milieu suggesting a potential mechanism for protection against HIV infection.

•Evidence for an Immunoqueiscent state at the FGT? Antiproteases may be ideal candidates for microbicide component

•Studies ongoing to determine mechanism of action and regulation of expression at FGT

Immunohistochemical stains of selected antiproteasesCystatin B

Serpin A1

A2ML1

Ball Lab

Adam BurgenerMax AbouKenzie Mogk

Keith Fowke /Julie L UM

Frank Plummer PHAC/UMPaul Sandstrom PHAC

Garret Westmacott PHACKristina Broliden Karolinska

Joshua Kimani University of NairobiWalter JaokoOmu Anzala

Women of the Pumwani, Majengo and Korogocho CSW Clinics,

Staff at the WHO Collaborative Center. Nairobi, Kenya