It has been shown that HIV/SIV preferentially replicates in the gut associated lymphoid tissue (GALT) which leads to immune activation and disease progression. Different sections of the gastrointestinal (GI) tract have unique biological functions with specialized lymphoid tissue composition and distribution, which may contribute differently to viral pathogenesis. We hypothesize that the GALT serves as an active viral replication site during the acute and AIDS stages of HIV/SIV infection and as a viral reservoir in long-term non-progressors (LTNP) and antiretroviral therapy (ART) treated individuals; this viral replication results in local immune activation which contributes to disease progression. The RNA and DNA were isolated from tissues along the GI tract of uninfected and SIV infected rhesus macaques in different disease stages with or without ART. Real-time PCR was utilized to measure viral RNA and DNA, and mRNAs of CD4, TNF-α, IL-6, IL-1β, and MyD88. Our results showed that SIV DNA/RNA were detected in all GI tissues from infected monkeys regardless of the disease stage and drug intervention. However, the viral load distribution profile in the GI tract varied from monkey to monkey. Despite the undetectable viral load in peripheral blood, both viral RNA and DNA were detected in GI tissues of ART treated monkeys. Compared to the uninfected monkeys, low levels of CD4 mRNA were detected in SIV infected monkeys, particularly LTNP. There is a positive association between viral load and mRNA levels of TNF-α, IL-6, and MyD88 in the stomach and duodenum. However, no association was observed between viral loads and IL-1β mRNA levels in any of the GI tissues examined. Data from this study indicates that the entire GI tract serves as a SIV replication site in all stages of infection, which leads to pro-inflammatory cytokine production and local inflammation. This study reveals the importance of the entire GI tract in HIV/SIV pathogenesis. Especially, in ART treated individuals with undetectable viral loads in blood, active viral replication in gut tissue may lead to development of drug resistant variants and faster progression to AIDS. This will have a profound impact on clinical intervention and public health as a whole.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04042011-183822 |
| Date | 29 June 2011 |
| Creators | Malzahn, Jessica M |
| Contributors | Phalguni Gupta, Yue Chen, Anthony Bauer |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04042011-183822/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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