HLA-associated immune pressure on Gag protein in CRF01_AE-infected individuals and its association with plasma viral load.
BACKGROUND
The human leukocyte antigen (HLA)-restricted cytotoxic T-lymphocyte (CTL) immune response is one of the major factors determining the genetic diversity of human immunodeficiency virus (HIV). There are few population-based analyses of the amino acid variations associated with the host HLA type and their clinical relevance for the Asian population. Here, we identified HLA-associated polymorphisms in the HIV-1 CRF01_AE Gag protein in infected married couples, and examined the consequences of these HLA-selected mutations after transmission to HLA-unmatched recipients.


RESULTS
One hundred sixteen HIV-1-infected couples were recruited at a government hospital in northern Thailand. The 1.7-kb gag gene was amplified and directly sequenced. We identified 56 associations between amino acid variations in Gag and HLA alleles. Of those amino acid variations, 35 (62.5%) were located within or adjacent to regions reported to be HIV-specific CTL epitopes restricted by the relevant HLA. Interestingly, a significant number of HLA-associated amino acid variations appear to be unique to the CRF01_AE-infected Thai population. Variations in the capsid protein (p24) had the strongest associations with the viral load and CD4 cell count. The mutation and reversion rates after transmission to a host with a different HLA environment varied considerably. The p24 T242N variant escape from B57/58 CTL had a significant impact on the HIV-1 viral load of CRF01_AE-infected patients.


CONCLUSIONS
HLA-associated amino acid mutations and the CTL selection pressures on the p24 antigen appear to have the most significant impact on HIV replication in a CRF01_AE-infected Asian population. HLA-associated mutations with a low reversion rate accumulated as a footprint in this Thai population. The novel HLA-associated mutations identified in this study encourage us to acquire more extensive information about the viral dynamics of HLA-associated amino acid polymorphisms in a given population as effective CTL vaccine targets.
Gesprasert
Goragoch
G
Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Wichukchinda
Nuanjun
N
Mori
Masahiko
M
Shiino
Teiichiro
T
Auwanit
Wattana
W
Sriwanthana
Busarawan
B
Pathipvanich
Panita
P
Sawanpanyalert
Pathom
P
Miura
Toshiyuki
T
Auewarakul
Prasert
P
Thitithanyanont
Arunee
A
Ariyoshi
Koya
K
D000483:Alleles; D001483:Base Sequence; D017931:DNA Primers; D015683:Gene Products, gag / Q000235:genetics*; D015658:HIV Infections / Q000276:immunology* / Q000635:transmission / Q000821:virology; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D009154:Mutation; D016133:Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019562:Viral Load
D017931:DNA Primers; D015683:Gene Products, gag; D006680:HLA Antigens