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Title: Evaluation of CD8+ T cell responses towards conserved HIV-1 epitopes in naturally infected and vaccinated individuals
Author: Ashraf, Ambreen
ISNI:       0000 0004 6423 739X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Human Immunodeficiency Virus (HIV) infection is a global public health priority. An effective HIV-1 vaccine strategy must overcome the enormous genetic diversity generated by the virus while inducing potent, long lasting immune responses. In this thesis, virus-specific cellular immune responses directed towards HIV conserved regions were evaluated using a validated IFN-γ enzyme-linked immunospot (ELISpot) assay and two sets of peptide panels based upon HIV-1 vaccine candidates. One panel was based on the 14 of the most highly conserved (HIVconsv – 806 amino acids) regions of the HIV-1 proteome and was designed to provide extensive coverage of subtypes A, B, C and D. The second panel represents Gag, Reverse Transcriptase (RT), Integrase (INT), Nef and Envelope sequences derived from a consensus subtype A reference (GRIN/Env). The purpose of this study was to examine the extent of T cell responses to HIV-1 epitopes elicited at different stages of HIV-1 infection and in vaccinees. Individuals infected with HIV-1 subtypes (A, B, C and D) from the UK, Rwanda, Uganda, and Zambia representing a wide range of genetic backgrounds were tested using a HIVconsv peptide matrix and GRIN pools. CD8 responses were identified across Gag, RT and INT and there was no apparent subtype specific bias in terms of recognition of both peptide panels (HIVconsv and GRIN/Env). GRIN appeared to be more antigenic because GRIN incorporated both conserved and variable epitopes compared to HIVconsv panel that only comprised conserved peptide sequences. Furthermore, there was no association between IFN-γ T cell responses and control of viraemia in early infection between viraemic controllers (VC) and viraemic progressors (VP). However, VC appeared to be slightly more polyfunctional than VP. Viral inhibition assay (VIA) employed to assess the vaccine specific responses demonstrated that conserved regions of the HIV-1 proteome could result in an increased ability to inhibit a panel of HIV-1 isolates in vitro. Although detection of a CD8+ T cell response against a particular epitope does not necessarily translate to protection, the conserved nature of HIV-1 epitopes suggests that these domains are immunogenic and might be important for viral function. Thus, these data support the inclusion of conserved sequences in any future vaccine candidate.
Supervisor: Hayes, Peter ; Kopycinski, Jakub ; Gotch, Frances Sponsor: International AIDS Vaccine Initiative
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral