HLA-associated clinical progression correlates with epitope reversion rates in early human immunodeficiency virus infection.
Human immunodeficiency virus type 1 (HIV-1) can evade immunity shortly after transmission to a new host but the clinical significance of this early viral adaptation in HIV infection is not clear. We present an analysis of sequence variation from a longitudinal cohort study of HIV adaptation in 189 acute seroconverters followed for up to 3 years. We measured the rates of variation within well-defined epitopes to determine associations with the HLA-linked hazard of disease progression. We found early reversion across both the gag and pol genes, with a 10-fold faster rate of escape in gag (2.2 versus 0.27 forward mutations/1,000 amino acid sites). For most epitopes (23/34), variation in the HLA-matched and HLA-unmatched controls was similar. For a minority of epitopes (8/34, and generally associated with HLA class I alleles that confer clinical benefit), new variants appeared early and consistently over the first 3 years of infection. Reversion occurred early at a rate which was HLA-dependent and correlated with the HLA class 1-associated relative hazard of disease progression and death (P = 0.0008), reinforcing the association between strong cytotoxic T-lymphocyte responses, viral fitness, and disease status. These data provide a comprehensive overview of viral adaptation in the first 3 years of infection. Our findings of HLA-dependent reversion suggest that costs are borne by some escape variants which may benefit the host, a finding contrary to a simple immune evasion paradigm. These epitopes, which are both strongly and frequently recognized, and for which escape involves a high cost to the virus, have the potential to optimize vaccine design.
Duda
A
A
Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, Oxford University, South Parks Road, Oxford OX1 3SY, United Kingdom.
Lee-Turner
L
L
Fox
J
J
Robinson
N
N
Dustan
S
S
Kaye
S
S
Fryer
H
H
Carrington
M
M
McClure
M
M
McLean
A R
AR
Fidler
S
S
Weber
J
J
Phillips
R E
RE
Frater
A J
AJ
D000595:Amino Acid Sequence; D015331:Cohort Studies; D018450:Disease Progression; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005805:Genes, MHC Class I; D015750:Genes, gag; D015751:Genes, pol; D006678:HIV / Q000235:genetics; D015658:HIV Infections / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans
D000939:Epitopes; D006680:HLA Antigens