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Functional Comparison of HIV-1 Vpu Alleles Derived from Elite Controller and Chronic Progressor Patients

Chen, Jingyan

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Human Immunodeficiency Virus type 1 (HIV-1) is the major causative agent of the AIDS epidemic. Several independent transmission events from monkeys to humans gave rise to different viral lineages that differ with respect to their ability to encode for accessory gene products that facilitate virus replication in the infected host. In particular, the vpu gene is unique to the HIV-1/SIVcpz lineage and not present in HIV-2 and most SIV isolates. Vpu is not essential for HIV-1 replication but intensively modulaties host immune components such as the HIV-1 primary entry receptor CD4, whose cell surface levels are reduced by Vpu. Uniquely, Vpu promotes the release of mature viral particle from infected cells by antagonizing the host restriction factor CD317/tetherin. Moreover, Vpu interferes with NF-ƙB signalling triggered by CD317/tetherin and reduces the cell surface exposure of MHC class I (MHC-I) and natural killer cells ligand NTB-A. While these Vpu activities have been established ex vivo, their relevance for HIV pathogenesis in the infected host remains unclear. In an attempt to correlate Vpu function with the clinical outcome of HIV-1 infection, we assessed here the functions of vpu alleles derived from two distinct clinical groups of treatment-naïve HIV-1 infected patients. While HIV-1 elite controllers (ECs) naturally control virus replication and keep the viral load below detectable level (<50 copies/ml), chronic progressors (CPs) display viral loads of more than 2 000 copies/ml. Both EC and CP Vpu alleles showed conserved and potent capacities to reduce cell surface levels of CD4 and CD317 molecules and to promote viral particle release. In contrast, EC Vpu alleles were less activitive in MHC-I and NTB-A downregulation than CP Vpu alleles and the antagonism of NF-kB signalling was not conserved in both patient groups. Sequence analysis of our Vpu alleles revealed the enrichment of killer-cell immunoglobulin-like receptor (KIR) KIR2DL2-associated footprints in EC Vpus, this polymorphism however did not explain the functional difference between EC and CP Vpus. These results suggest downregulation of cell surface CD4 and antagonism of the particle release restriction by CD317 as important in vivo functions of Vpu. Since attenuated Vpu alleles were more frequent in ECs than in CPs, at least a subgroup of EC Vpu alleles may be under selection pressure resulting in adaptation of Vpu that is associated with a mild fitness cost. Whether the functional constrains of EC Vpu alleles contribute to the suppression of HIV-1 in these patients warrants further investigation.

Item Type: Dissertation
Supervisor: Fackler, Prof. Dr. Oliver T.
Date of thesis defense: 29 September 2014
Date Deposited: 17 Oct 2014 06:40
Date: 2014
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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