TY - JOUR
T1 - HLA-associated clinical progression correlates with epitope reversion rates in early human immunodeficiency virus infection
AU - Duda, A.
AU - Lee-Turner, L.
AU - Fox, J.
AU - Robinson, N.
AU - Dustan, S.
AU - Kaye, S.
AU - Fryer, H.
AU - Carrington, M.
AU - McClure, M.
AU - Mclean, A. R.
AU - Fidler, S.
AU - Weber, J.
AU - Phillips, R. E.
AU - Frater, A. J.
AU - Breckenridge, A.
AU - Conlon, C.
AU - Cooper, D.
AU - Conradie, F.
AU - Kaldor, J.
AU - Schechter, M.
AU - Claydon, P.
AU - Kaleebu, P.
AU - Ramjee, G.
AU - Ssali, F.
AU - Tambussi, G.
PY - 2009/2
Y1 - 2009/2
N2 - 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.
AB - 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.
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U2 - 10.1128/JVI.01545-08
DO - 10.1128/JVI.01545-08
M3 - Article
C2 - 19019964
AN - SCOPUS:59749085611
VL - 83
SP - 1228
EP - 1239
JO - Journal of Virology
JF - Journal of Virology
SN - 0022-538X
IS - 3
ER -