Aisha Nazli, Olivia Chan and Charu Kaushic,

1
Integrity of mucosal epithelial barrier function
is breached by exposure to HIV-1
Aisha Nazli, Olivia Chan and Charu Kaushic,
2
Contribution of HIV invasion sites to global HIV
infections
Hladik and McElrath, 2008
3
Cervix (Longitudinal Section)
Endocervix
Glands
Vessels
Transformation Zone
Ectocervix
4
Genital and Intestinal tracts (columnar
epithelial cells connected by tight junctions)
5
HIV Effect on mucosal permeability
-Leakage in gut Diarrhea- one of the common
symptom during primary HIV Infection. Schmitz et
al. AIDS 2002. -Microbial translocation is a
cause of systemic activation in chronic HIV
infection. Brenchley et al. Nature Medicine.
2006. -Impairment of the intestinal barrier is
evident in untreated but absent in suppressively
treated HIV-infected patients. Epple et al, Gut,
2009.
Cause/Mechanism of this leakage?
6
HIV exposure on epithelial monolayers
causes significant reduction in Transepithelial
Resistance
(p 0.001)
7
Exposure to HIV-1 does not compromise viability
of epithelium
8
Exposure to HIV-1 disrupts tight junction proteins
9
HIV but not HSV-2 causes disruption of tight
junctions
4 hours post-HIV exposure
4 hours post HSV-2 infection
Mock-exposure
Magnification 2520X
10
HIV protein Gp120 treatment leads to impairment
of barrier function
(Magnification 2520X)
11
Exposure to HIV upregulates inflammatory cytokine
by ECs
T84 Intestinal epithelial cells
Endometrial epithelial cells
12
Neutralization of TNF-a abrogates effect of HIV
on epithelial barrier
13
HIV exposure causes barrier dysfunction and
results in bacterial translocation
14
Translocation of virus through endometrial
epithelial monolayers become evident 6 hours post
HIV exposure
15
Conclusion

• Exposure to HIV-1 directly decreases barrier
  function of mucosal epithelial cells evident by
  reduced trans-epithelial resistance and
  disruption of tight junction.
• The disruption in barrier functions was mediated
  by increased production of inflammatory
  cytokines, especially TNF-a by both intestinal
  and genital epithelial cells.
• 3. Disruption of tight junctions and increased
  permeability is probably directly mediated by
  HIV envelope components and not linked to viral
  replication.
• 4. The impairment of barrier function is
  associated with small but significant
  translocation of bacteria and virus across
  epithelial monolayers.
• 5. Bacterial and viral translocation across
  leakymucosal epithelium could be relevant to
  immune activation seen in HIV infected
  individuals as well as mucosal transmission of
  HIV-1, especially in presence of local
  inflammation.

16
ACKNOWLEDGEMENT
Human Subjects Pathologists Olivia Chan Susanna
Goncharova Dr Charu Kaushic