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Studies on the cellular factors and hormones controlling HIV-1 transmission in an organ culture model

Sankapal, Soni Ramachandra (2015) Studies on the cellular factors and hormones controlling HIV-1 transmission in an organ culture model. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

There is very little information available on how HIV-1 transmits through mucosal epithelial layer since it does not express HIV-1 receptor. Overall goal of the project is to elucidate the role of cellular factors and reproductive hormones on HIV-1 transmission across ectocervical and colonic mucosa in an organ culture model. We hypothesize that upon exposure to HIV-1, a complex signal transduction network is activated in epithelial cells, which leads to compromised barrier function by disrupted tight junctions and expression of immune mediators, which would recruit immune cells towards the epithelial layer for replication of virus. Furthermore, reproductive hormone might have an effect on HIV-1 acquisition risk. To test the hypothesis, we evaluated in context of tissue structure whether HIV-1 induces tight junction disruption in ectocervical and colon epithelial cells, examined the cellular factors, including inflammatory cytokines that are involved in HIV-1 transmission across ectocervical epithelia and evaluated the effect of reproductive hormone on HIV-1 transmission. Our results in aim 1 showed that after exposure to HIV-1, no significant changes in the tight junction/adherens junction protein expression were observed in ectocervical and colon epithelia. However, these tissues were infected after exposure to HIV-1. Our data thus indicate that HIV-1 transverses the ectocervical/colon mucosal epithelia without profoundly disrupting the tight junction/adherens junction between epithelial cell. In aim 2, we found that after HIV-1 exposure, the level of CXCL10 and CXCL11 messages in ectocervical epithelia were upregulated and such induction of cytokines in ectocervical epithelia was dependent on HIV-1 infectivity. Furthermore, we measured the expression level of cellular factors in HIV-1 exposed ectocervical epithelia by next generation sequencing. Our results indicate that, cellular genes like IL36A, FMO2, CXCL10, MUC1, SAA1 and IL8 were differentially expressed in ectocervical epithelia exposed to HIV-1 compared to controls. These results suggest that exposure to HIV-1 induces cytokine production and other cellular factors in epithelial cells. In aim 3, we investigated the impact of reproductive hormones on the risk of HIV-1 acquisition by analyzing the susceptibility of ectocervical/vaginal tissues to HIV-1 infection and by comparing the epithelial thickness/tight junction protein expression in ectocervical/vaginal tissues at different phases of menstrual cycle. Our results showed no difference in HIV-1 susceptibility, epithelial layer thickness and tight junction/adherence junction protein expression levels in ectocervical/vaginal tissues at different stages of the menstrual cycle. Taken together, our results suggest that risk of HIV-1 infection in the ectocervical/vaginal region does not vary over the course of menstrual cycle. These findings are of public health importance because they expand our understanding on mechanism of atraumatic HIV-1 transmission in mucosal area that may be important for developing effective strategies for preventing HIV-1 transmission.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Sankapal, Soni Ramachandrasos28@pitt.eduSOS28
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorChen, Yuecheny@pitt.eduCHENY
Committee CoChairGupta, Phalgunipgupta1@pitt.eduPGUPTA1
Committee MemberCoyne, Carolyn Bcoynec2@pitt.eduCOYNEC2
Committee MemberReinhart, Todd A.reinhar@pitt.eduREINHAR
Date: 28 September 2015
Date Type: Publication
Defense Date: 20 July 2015
Approval Date: 28 September 2015
Submission Date: 22 July 2015
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 110
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Tight junction, cervical and colonic epithelium, HIV-1 transmission, cytokines, menstrual cycle, reproductive hormones
Date Deposited: 28 Sep 2015 19:00
Last Modified: 15 Nov 2016 14:29
URI: http://d-scholarship.pitt.edu/id/eprint/25742

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