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Dynamics of HIV-1 tropism during immune recovery driven by combination antiretroviral therapy

Bader, Joëlle. Dynamics of HIV-1 tropism during immune recovery driven by combination antiretroviral therapy. 2015, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_11588

Abstract

HIV is characterized by the infection of CD4 T-cells and the accompanied attack of the immune system. Successful infection thus requires the binding to the CD4 receptor and a chemokine receptor, either CCR5 or CXCR4. In the early phase of infection the virus almost exclusively uses the CCR5-receptor. Only later during disease progression CXCR4-tropic viruses are found as majority in up to 50% of all patients. They associate with a more rapid CD4 T-cell loss and accelerated disease progression. The underlying causes of this change in the viral tropism are not known. As a significant percentage of patients only achieve a suboptimal CD4 T-cell recovery while treated, the viral tropism might play a role for such an incomplete immune response. The aim of this thesis was to follow the viral tropism dynamics, especially the abundance of CXCR4-tropic cell-associated viruses during phases of immune recovery by combination antiretroviral therapy with the intention to understand and help improving the immune situation during therapy. Patient samples from the Swiss HIV Cohort Study were used to asses the viral tropism before and after several years of treatment initiation. As during therapy free plasma virus was fully suppressed, analysis focus laid on integrated viral genomes. This work found that CXCR4-tropic viral variants are not inevitably associated with an impaired CD4 T-cell recovery as most of the viruses with a pre-treatment CXCR4 tropism presented a CCR5-tropism during therapy. Furthermore, it identified that the frequency of CXCR4-tropic viruses under therapy generally decreases and that therefore the proviral reservoir mostly persists of CCR5-tropic viruses. Based on the fact that all free viral variants were equally suppressed these findings suggest the involvement of the immune system, which appears to selectively target CXCR4-tropic infected cells. If a competent immune system were capable of preferentially controlling CXCR4-tropic viruses, this would also explain why these variants mostly appear later during disease when the damage of the immune system is accelerated. As a consequence, the findings discussed in this thesis support early therapy initiation as strategy to prevent the later occurrence of CXCR4-tropic HIV. Furthermore, remaining CCR5-tropic viruses may most effectively be suppressed by additional therapy options of CCR5-receptor antagonists.
Advisors:Affolter, Markus and Klimkait, Thomas and Stöckle, Marcel
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Cell Biology (Affolter)
Item Type:Thesis
Thesis no:11588
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (93 Seiten)
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:59
Deposited On:27 May 2016 08:05

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