Characterisation of HIV reservoirs in blood and gut association lymphoid tissue
File(s)
Author(s)
Thornhill, John
Type
Thesis
Abstract
Antiretroviral therapy (ART) has dramatically improved survival for people living with HIV (PLWH). However, a stable pool of latently infected cells precludes a cure. Initiation of ART during primary infection (PHI) has been used as a strategy to limit seeding of the HIV reservoir
and enhance immune recovery. Gut-associated lymphoid tissue (GALT) is targeted early in HIV infection with significant immune damage and remains one of the principal sites of latent HIV infection on ART. However, data characterising immune recovery & the HIV reservoir in the GALT of these early treated individuals are lacking.
Using concurrent peripheral blood (PBMC) and biopsy samples from the terminal ileum and rectum, I characterised the HIV reservoir across anatomical sites in treated PHI. I tested the hypothesis that ART initiated in PHI results in normalisation of immune parameters across
anatomical sites. Furthermore, I characterised cellular populations known to support HIV persistence and tested for associations between HIV DNA and gut markers of inflammation and immune dysfunction.
This thesis provides evidence of compartmentalised immune recovery in treated PHI with enhanced recovery in the PBMC compartment compared to GALT. Furthermore, the burden of latent HIV infection was highest in the terminal ileum compared to all other sites. Markers
of inflammation, bacterial translocation and TFH lineage associated with HIV DNA in GALT while markers of T cell exhaustion did not.
Even when started in PHI, ART did not normalise markers of immune function in GALT, and HIV DNA persisted at high levels in GALT despite years of suppressive ART. Bacterial
translocation and the B cell - T cell interaction may contribute to HIV persistence in GALT. A better understanding of the drivers of viral persistence and immune dysfunction in GALT can inform the design of future HIV cure approaches.
and enhance immune recovery. Gut-associated lymphoid tissue (GALT) is targeted early in HIV infection with significant immune damage and remains one of the principal sites of latent HIV infection on ART. However, data characterising immune recovery & the HIV reservoir in the GALT of these early treated individuals are lacking.
Using concurrent peripheral blood (PBMC) and biopsy samples from the terminal ileum and rectum, I characterised the HIV reservoir across anatomical sites in treated PHI. I tested the hypothesis that ART initiated in PHI results in normalisation of immune parameters across
anatomical sites. Furthermore, I characterised cellular populations known to support HIV persistence and tested for associations between HIV DNA and gut markers of inflammation and immune dysfunction.
This thesis provides evidence of compartmentalised immune recovery in treated PHI with enhanced recovery in the PBMC compartment compared to GALT. Furthermore, the burden of latent HIV infection was highest in the terminal ileum compared to all other sites. Markers
of inflammation, bacterial translocation and TFH lineage associated with HIV DNA in GALT while markers of T cell exhaustion did not.
Even when started in PHI, ART did not normalise markers of immune function in GALT, and HIV DNA persisted at high levels in GALT despite years of suppressive ART. Bacterial
translocation and the B cell - T cell interaction may contribute to HIV persistence in GALT. A better understanding of the drivers of viral persistence and immune dysfunction in GALT can inform the design of future HIV cure approaches.
Version
Open Access
Date Issued
2018-07
Date Awarded
2018-11
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Fidler, Sarah
Frater, John
Taylor, Graham
Sponsor
Medical Research Council
Grant Number
WMND/P56121
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)