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HIV-1 Reservoir Formation, Stability and Dynamics during early Therapy

Otte, Fabian. HIV-1 Reservoir Formation, Stability and Dynamics during early Therapy. 2021, Doctoral Thesis, University of Basel, Faculty of Science.

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Abstract

After an infection event, the Human immunodeficiency virus (HIV) can rapidly seed at its initial contact zone within few days leading to systemic spread in the whole body. It is the combination of high propagation rates and the error-prone viral replication that drives a rapid viral evolution and evasion of an effective immune response. Modern combination HIV therapy can impede such a continuous adaptation of the virus through sustained virus suppression. However, the very rapid return of replicating virus in the blood upon stop of therapy, is a most obvious indicator of active or activatable “sanctuaries”. Lymphoid tissues and especially the gut associated lymphatic tissue (GALT) play key roles in viral persistence. In order to infect the main target, CD4-positive cells, HIV needs to bind a chemokine receptor, either CCR5 or CXCR4, prior to fusing with its target cell. During early periods of the infection, the virus predominantly uses CCR5. In the untreated host, about 50% of patients experience a shift to a dominance of CXCR4-tropic (X4) viruses, associated with higher CD4 depletion rates and an accelerated disease progression. In contrast, under successful therapy CXCR4 tropism does not increase over time but rather seems to become actively eliminated. To address this somewhat unexpected observation, peripheral blood mononuclear cells (PBMCs) were used to assess their contribution to the viral reservoir. The aim was to identify predictive properties of those “circulating cells”, which have the capacity to carry (viral) information from the periphery to distant site of persistence for understanding the dynamics of HIV infections during early treatment periods. For single cell immune characterization, a new methodology called GERDA (Gag and Envelope Reactivation Detection Assay) was established and validated by genetic and functional reservoir assays to find potential infectious cells. To dissect the contribution of cellular reservoirs, viral activity was measured on the level of DNA, RNA and protein. It confirmed that intracellular viral activity quickly declines after initiation of ART. Furthermore, most peripheral cells did not show high viral gene activity in the cytoplasm despite detectable plasma viral load and even when sampling right after diagnosis. This strongly suggests that the main active reservoir remains outside the periphery. In all patients of the study, the dominating virus variant at time of diagnosis was also found inside cells in the form of integrated viral genomes and did not change in the first months of therapy. For individuals with signs of ongoing viral activity, most actively replicating viruses were found in central memory cells, i.e. lymphoid homing cells and not in gut homing cells.
Overall, this study introduces a new concept of reservoir characterization using PBMCs in circulating blood for identifying by use of “homing markers” crucial body compartments and actively infected cell populations that will help to explain residing viral activity and potential obstacles for the eradication of HIV and towards a cure.
Advisors:Klimkait, Thomas and Dehio, Christoph and Ciuffi, Angela Teresa
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Medical Microbiology > Molecular Virology (Klimkait)
05 Faculty of Science > Departement Biozentrum
UniBasel Contributors:Klimkait, Thomas and Dehio, Christoph
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13987
Thesis status:Complete
Number of Pages:127
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss139879
edoc DOI:
Last Modified:05 Mar 2021 05:30
Deposited On:04 Mar 2021 07:56

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