Full Text Available
Note: Clicking the button above will open the full text document at the original institutional repository in a new window.
Compartmentalization, adaptive evolution and therapeutic response of HIV-1 in the gastrointestinal tract (GIT) of African patients infected with Subtype C: implications for the enhancement of therapeutic efficacy
Thesis (PhD)--University of Pretoria, 2014.
Saved in:
| Other Authors: | |
|---|---|
| Format: | Thesis |
| Language: | English |
| Published: |
University of Pretoria
2015
|
| Subjects: | |
| Tags: |
No Tags, Be the first to tag this record!
|
| _version_ | 1867613498407649280 |
|---|---|
| access_status_str | Open Access |
| author2 | Cassol, Sharon |
| author_browse | Cassol, Sharon |
| author_facet | Cassol, Sharon |
| collection | Thesis |
| dc_rights_str_mv | © 2014 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Thesis (PhD)--University of Pretoria, 2014. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/43156 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:37:06.348Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2015 |
| publishDateRange | 2015 |
| publishDateSort | 2015 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/43156 Compartmentalization, adaptive evolution and therapeutic response of HIV-1 in the gastrointestinal tract (GIT) of African patients infected with Subtype C: implications for the enhancement of therapeutic efficacy Cassol, Sharon thakgalo03@gmail.com De Oliveira, Tulio Mahasha, Phetole Walter Human immunodeficiency virus type 1 (HIV-1) Gastrointestinal tract Antiretroviral therapy (ART) Viral RNA quasispecies Genetic diversity UCTD CD4 reconstitution Intestine Africa Immune activation Thesis (PhD)--University of Pretoria, 2014. BACKGROUND : Due to its continuous exposure to food antigens and microbes, the gastrointestinal tract (GIT) is in a constant state of low level immune activation and contains an abundance of activated CCR5+CD4+ T lymphocytes, the primary target HIV-1. As a result, the GIT is a site of intense viral replication and severe CD4+ T cell depletion, a process that begins during primary HIV-1 infection and continues at a reduced rate during chronic infection in association with increased production of pro-inflammatory cytokines, a breakdown in the epithelial barrier, microbial translocation, systemic immune activation and the continued recruitment and infection of new target cells. AntiRetroviral Therapy (ART) is only partially effective in reversing these pathogenic changes. Despite the importance of the GIT in HIV-1 pathogenesis, and as a reservoir of persistent virus during ART, little is known about the diversity of HIV-1 in the GIT, or how different tissues in the GIT respond to ART. OBJECTIVES : Primary objectives of this thesis were to: 1) characterize the diversity of HIV-1 RNA variants in different parts of the GIT; 2) determine whether there is compartmentalized evolution of HIV-1 RNA variants in the GIT and whether these variants are likely to have different biological properties; 3) investigate the impact of ART on immune restoration in the GIT. METHODS : A prospective study of the duodenum, jejunum, ileum and colon of African AIDS patients with chronic diarrhea and/or weight loss, sampled before and during 6 months of ART. RNA extracted from gut biopsies was reverse transcribed and PCR amplified. Env and gag PCR fragments were cloned, sequenced and subjected to extensive phylogenetic analysis; pol PCR fragments were analyzed for drug resistance. CD4+, CD8+ and CD38+CD8+ T cells levels in biopsies collected at baseline (duodenum, jejunum, ileum and colon) and after 3 (duodenum) and 6 (duodenum and colon) months of ART were quantified by flow cytometry and immunohistochemistry, plasma and tissue VL by the Nuclisens assay. RESULTS : Viral diversity varied in different regions of the GIT with env HIV-1 RNA variants being significantly more diverse than gag variants. Gag HIV-1 RNA variants were widely dispersed among all tissue compartments. Some env variants formed tight monophyletic clusters of closely related viral quasispecies, especially in the colon, a finding that is suggestive of compartmentalized viral replication and adaptive evolution. CD4+ T cell and VL levels were significantly lower, while CD8+ including activated CD38+CD8+ T cell levels were higher in the duodenum and jejunum versus the colon. After 6 months of ART, a significant but incomplete recovery of CD4+ T cells was observed in the colon but not in the duodenum. Failed restoration of CD4+ T cells in the duodenum was associated with non-specific enteritis and CD8+ T cell activation. CONCLUSIONS : These results advance our understanding of the GIT as a host-pathogen interface by providing new insights into the diversity, evolution and dissemination of HIV-1 variants in the GIT. Strategies aimed at decreasing immune activation, especially in the small intestine, may be highly beneficial in enhancing the therapeutic efficacy of ART. lk2014 Immunology PhD Unrestricted 2015-01-19T12:11:08Z 2015-01-19T12:11:08Z 2014/12/12 2014 Thesis Mahasha, P 2014, Compartmentalization, adaptive evolution and therapeutic response of HIV-1 in the gastrointestinal tract (GIT) of African patients infected with Subtype C: implications for the enhancement of therapeutic efficacy, PhD Thesis, University of Pretoria, Pretoria, viewed yymmdd <http://hdl.handle.net/2263/43156> D14/9/78 http://hdl.handle.net/2263/43156 en © 2014 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | Human immunodeficiency virus type 1 (HIV-1) Gastrointestinal tract Antiretroviral therapy (ART) Viral RNA quasispecies Genetic diversity UCTD CD4 reconstitution Intestine Africa Immune activation Compartmentalization, adaptive evolution and therapeutic response of HIV-1 in the gastrointestinal tract (GIT) of African patients infected with Subtype C: implications for the enhancement of therapeutic efficacy |
| title | Compartmentalization, adaptive evolution and therapeutic response of HIV-1 in the gastrointestinal tract (GIT) of African patients infected with Subtype C: implications for the enhancement of therapeutic efficacy |
| title_full | Compartmentalization, adaptive evolution and therapeutic response of HIV-1 in the gastrointestinal tract (GIT) of African patients infected with Subtype C: implications for the enhancement of therapeutic efficacy |
| title_fullStr | Compartmentalization, adaptive evolution and therapeutic response of HIV-1 in the gastrointestinal tract (GIT) of African patients infected with Subtype C: implications for the enhancement of therapeutic efficacy |
| title_full_unstemmed | Compartmentalization, adaptive evolution and therapeutic response of HIV-1 in the gastrointestinal tract (GIT) of African patients infected with Subtype C: implications for the enhancement of therapeutic efficacy |
| title_short | Compartmentalization, adaptive evolution and therapeutic response of HIV-1 in the gastrointestinal tract (GIT) of African patients infected with Subtype C: implications for the enhancement of therapeutic efficacy |
| title_sort | compartmentalization adaptive evolution and therapeutic response of hiv 1 in the gastrointestinal tract git of african patients infected with subtype c implications for the enhancement of therapeutic efficacy |
| topic | Human immunodeficiency virus type 1 (HIV-1) Gastrointestinal tract Antiretroviral therapy (ART) Viral RNA quasispecies Genetic diversity UCTD CD4 reconstitution Intestine Africa Immune activation |
| url | http://hdl.handle.net/2263/43156 |