Evolution and transmission of stable CTL escape mutations in HIV infection

TY - JOUR

T1 - Evolution and transmission of stable CTL escape mutations in HIV infection

AU - Goulder, P J

AU - Brander, C

AU - Tang, Y

AU - Tremblay, C

AU - Colbert, R A

AU - Addo, M M

AU - Rosenberg, E S

AU - Nguyen, T

AU - Allen, R

AU - Trocha, A

AU - Altfeld, M

AU - He, S

AU - Bunce, M

AU - Funkhouser, R

AU - Pelton, S I

AU - Burchett, S K

AU - McIntosh, K

AU - Korber, B T

AU - Walker, B D

PY - 2001/7/19

Y1 - 2001/7/19

N2 - Increasing evidence indicates that potent anti-HIV-1 activity is mediated by cytotoxic T lymphocytes (CTLs); however, the effects of this immune pressure on viral transmission and evolution have not been determined. Here we investigate mother-child transmission in the setting of human leukocyte antigen (HLA)-B27 expression, selected for analysis because it is associated with prolonged immune containment in adult infection. In adults, mutations in a dominant and highly conserved B27-restricted Gag CTL epitope lead to loss of recognition and disease progression. In mothers expressing HLA-B27 who transmit HIV-1 perinatally, we document transmission of viruses encoding CTL escape variants in this dominant Gag epitope that no longer bind to B27. Their infected infants target an otherwise subdominant B27-restricted epitope and fail to contain HIV replication. These CTL escape variants remain stable without reversion in the absence of the evolutionary pressure that originally selected the mutation. These data suggest that CTL escape mutations in epitopes associated with suppression of viraemia will accumulate as the epidemic progresses, and therefore have important implications for vaccine design.

AB - Increasing evidence indicates that potent anti-HIV-1 activity is mediated by cytotoxic T lymphocytes (CTLs); however, the effects of this immune pressure on viral transmission and evolution have not been determined. Here we investigate mother-child transmission in the setting of human leukocyte antigen (HLA)-B27 expression, selected for analysis because it is associated with prolonged immune containment in adult infection. In adults, mutations in a dominant and highly conserved B27-restricted Gag CTL epitope lead to loss of recognition and disease progression. In mothers expressing HLA-B27 who transmit HIV-1 perinatally, we document transmission of viruses encoding CTL escape variants in this dominant Gag epitope that no longer bind to B27. Their infected infants target an otherwise subdominant B27-restricted epitope and fail to contain HIV replication. These CTL escape variants remain stable without reversion in the absence of the evolutionary pressure that originally selected the mutation. These data suggest that CTL escape mutations in epitopes associated with suppression of viraemia will accumulate as the epidemic progresses, and therefore have important implications for vaccine design.

KW - Adult

KW - Child

KW - DNA, Viral

KW - Disease Progression

KW - Epitopes, T-Lymphocyte/genetics

KW - Female

KW - HIV Infections/genetics

KW - HIV-1/genetics

KW - HLA-B27 Antigen/immunology

KW - Histocompatibility Testing

KW - Humans

KW - Infectious Disease Transmission, Vertical

KW - Mutation

KW - T-Lymphocytes, Cytotoxic/immunology

U2 - 10.1038/35085576

DO - 10.1038/35085576

M3 - SCORING: Journal article

C2 - 11460164

VL - 412

SP - 334

EP - 338

JO - NATURE

JF - NATURE

SN - 0028-0836

IS - 6844

ER -