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Early Events of SIVsab Mucosal Transmission in African Green Monkeys

Raehtz, Kevin (2019) Early Events of SIVsab Mucosal Transmission in African Green Monkeys. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Unlike HIV infection in humans, SIV infection is generally nonpathogenic in natural hosts, such as African green monkeys (AGMs), despite high life-long viral replication. Previous research has indicated that key events occurring early during SIV infection of natural hosts may influence the pathogenic outcome of infection. The main objective of this project was to characterize these early events following mucosal transmission in a natural host. To this goal, 29 adult male AGMs were intrarectally infected with SIVsab92018 and serially sacrificed at various stage of acute and early chronic SIV infection. In order to characterize viral spread and replication, an extensive survey of plasma and tissue viral loads was performed. SIV replication and dissemination from the site of inoculation occurred very rapidly, possibly even simultaneously, resulting in a very rapid virus seeding of virtually every tissue compartment. However, immune activation and inflammation in response to infection were limited and largely transient. As control of inflammation is associated with preservation of the integrity of the gut epithelium, which is damaged during acute pathogenic HIV/SIV infections by viral replication in the GALT and bystander effects, a wide variety of markers for immune activation, apoptosis, fibrosis and epithelial integrity were evaluated in the AGM gut. No evidence of disruption of the epithelial barrier in the gut or the translocation of highly inflammatory microbial byproducts from the gut lumen was found. Transcriptomic analysis was performed to evaluate gene expression in the gut of AGMs versus rhesus macaques (RMs) intrarectally inoculated with pathogenic SIVmac251. We identified a unique macrophage-mediated wound healing response, which occurred in AGMs and was absent in the RMs which would allow maintenance of the gut mucosa through exquisite repair of virally induced damage during early SIV infection. We concluded that through a combination of repair and low levels of immune activation, AGMs are able to maintain gut epithelial integrity despite high acute viral replication. As microbial translocation and the resultant chronic inflammation are the major drivers of pathogenesis, prevention of these events by preservation of gut homeostasis are a crucial component to avoiding disease progression in natural hosts.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Raehtz, Kevinkdr26@pitt.edukdr260000-0002-0687-7714
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKhan, Saleem Akhan@pitt.eduKHAN
Thesis AdvisorApetrei, Cristianapetreic@pitt.edu
Committee MemberZandrea, Ambrosezaa4@pitt.edu
Committee MemberRinaldo, Charlesrinaldo@pitt.edu
Committee MemberEstes, Jacobestesja@ohsu.edu
Committee MemberKeele, Brandonkeelebf@mail.nih.gov
Date: 20 September 2019
Date Type: Publication
Defense Date: 23 July 2019
Approval Date: 20 September 2019
Submission Date: 19 August 2019
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 234
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Simian immunodeficiency virus, nonhuman primates, natural hosts, pathogenic infection, nonpathogenic infection, AIDS, microbial translocation, enteropathy, chronic inflammation, gut integrity, gut epithelium, wound healing
Date Deposited: 20 Sep 2019 18:31
Last Modified: 20 Sep 2019 18:31
URI: http://d-scholarship.pitt.edu/id/eprint/37427

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