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Disease progression despite protective HLA expression in an HIV-infected transmission pair

Title: Disease progression despite protective HLA expression in an HIV-infected transmission pair
Authors: Brener, J
Gall, A
Batorsky, R
Riddell, L
Buus, S
Leitman, E
Kellam, P
Allen, T
Goulder, P
Matthews, PC
Item Type: Journal Article
Abstract: Background The precise immune responses mediated by HLA class I molecules such as HLA-B*27:05 and HLA-B*57:01 that protect against HIV disease progression remain unclear. We studied a CRF01_AE clade HIV infected donor-recipient transmission pair in which the recipient expressed both HLA-B*27:05 and HLA-B*57:01. Results Within 4.5 years of diagnosis, the recipient had progressed to meet criteria for antiretroviral therapy initiation. We employed ultra-deep sequencing of the full-length virus genome in both donor and recipient as an unbiased approach by which to identify specific viral mutations selected in association with progression. Using a heat map method to highlight differences in the viral sequences between donor and recipient, we demonstrated that the majority of the recipient’s mutations outside of Env were within epitopes restricted by HLA-B*27:05 and HLA-B*57:01, including the well-studied Gag epitopes. The donor, who also expressed HLA alleles associated with disease protection, HLA-A*32:01/B*13:02/B*14:01, showed selection of mutations in parallel with disease progression within epitopes restricted by these protective alleles. Conclusions These studies of full-length viral sequences in a transmission pair, both of whom expressed protective HLA alleles but nevertheless failed to control viremia, are consistent with previous reports pointing to the critical role of Gag-specific CD8+ T cell responses restricted by protective HLA molecules in maintaining immune control of HIV infection. The transmission of subtype CRF01_AE clade infection may have contributed to accelerated disease progression in this pair as a result of clade-specific sequence differences in immunodominant epitopes.
Issue Date: 30-Jun-2015
Date of Acceptance: 2-Jun-2015
URI: http://hdl.handle.net/10044/1/69574
DOI: https://dx.doi.org/10.1186/s12977-015-0179-z
ISSN: 1742-4690
Publisher: BioMed Central
Journal / Book Title: Retrovirology
Volume: 12
Issue: 1
Copyright Statement: © 2015 Brener et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Keywords: Science & Technology
Life Sciences & Biomedicine
Virology
HIV-1
HLA
CTL response
CRF01_AE Clade
Transmission pair
Ultra-deep sequencing
IMMUNODEFICIENCY-VIRUS TYPE-1
T-CELL RESPONSES
VIRAL REPLICATION CAPACITY
ESCAPE MUTATIONS
CLASS-I
IMMUNE CONTROL
GAG
EPITOPES
ALLELES
ASSOCIATIONS
Adult
Disease Progression
Epitopes
Family Characteristics
Female
Gene Expression
HIV
HIV Infections
HLA-B Antigens
HLA-B27 Antigen
Humans
Male
Molecular Sequence Data
Mutation, Missense
Sequence Analysis, DNA
gag Gene Products, Human Immunodeficiency Virus
1103 Clinical Sciences
Publication Status: Published
Article Number: 55
Online Publication Date: 2015-06-30
Appears in Collections:Department of Medicine



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