Substantial differences in specificity of HIV-specific cytotoxic T cells in acute and chronic HIV infection

TY - JOUR

T1 - Substantial differences in specificity of HIV-specific cytotoxic T cells in acute and chronic HIV infection

AU - Goulder, P J

AU - Altfeld, M A

AU - Rosenberg, E S

AU - Nguyen, T

AU - Tang, Y

AU - Eldridge, R L

AU - Addo, M M

AU - He, S

AU - Mukherjee, J S

AU - Phillips, M N

AU - Bunce, M

AU - Kalams, S A

AU - Sekaly, R P

AU - Walker, B D

AU - Brander, C

PY - 2001/1/15

Y1 - 2001/1/15

N2 - Cytotoxic T lymphocytes (CTLs) play a vital part in controlling viral replication during human viral infections. Most studies in human infections have focused on CTL specificities in chronic infection and few data exist regarding the specificity of the initial CTL response induced in acute infection. In this study, HIV-1 infection in persons expressing human histocompatibility leukocyte antigen (HLA)-A*0201 was used as a means of addressing this issue. In chronic infection, the dominant HLA-A*0201-restricted CTL response is directed towards the epitope SLYNTVATL ("SL9") in p17 Gag (residues 77-85). This epitope is targeted by 75% of HLA-A*0201-positive adults, and the magnitude of this A*0201-SL9 response shows a strong negative association with viral load in progressive infection. Despite using the highly sensitive peptide-major histocompatibility complex tetramer and intracellular cytokine assays, responses to the SL9 epitope were not detectable in any of 11 HLA-A*0201-positive subjects with acute HIV-1 infection (P = 2 x 10(-6)), even when assays were repeated using the SL9 peptide variant that was encoded by their autologous virus. In contrast, multiple responses (median 3) to other epitopes were evident in 7 of the 11 A*0201-positive subjects. Longitudinal study of two subjects confirmed that the A*0201-SL9 response emerged later than other CTL responses, and after viral set point had been reached. Together, these data show that the CTL responses that are present and that even may dominate in chronic infection may differ substantially from those that constitute the initial antiviral CTL response. This finding is an important consideration in vaccine design and in the evaluation of vaccine candidates.

AB - Cytotoxic T lymphocytes (CTLs) play a vital part in controlling viral replication during human viral infections. Most studies in human infections have focused on CTL specificities in chronic infection and few data exist regarding the specificity of the initial CTL response induced in acute infection. In this study, HIV-1 infection in persons expressing human histocompatibility leukocyte antigen (HLA)-A*0201 was used as a means of addressing this issue. In chronic infection, the dominant HLA-A*0201-restricted CTL response is directed towards the epitope SLYNTVATL ("SL9") in p17 Gag (residues 77-85). This epitope is targeted by 75% of HLA-A*0201-positive adults, and the magnitude of this A*0201-SL9 response shows a strong negative association with viral load in progressive infection. Despite using the highly sensitive peptide-major histocompatibility complex tetramer and intracellular cytokine assays, responses to the SL9 epitope were not detectable in any of 11 HLA-A*0201-positive subjects with acute HIV-1 infection (P = 2 x 10(-6)), even when assays were repeated using the SL9 peptide variant that was encoded by their autologous virus. In contrast, multiple responses (median 3) to other epitopes were evident in 7 of the 11 A*0201-positive subjects. Longitudinal study of two subjects confirmed that the A*0201-SL9 response emerged later than other CTL responses, and after viral set point had been reached. Together, these data show that the CTL responses that are present and that even may dominate in chronic infection may differ substantially from those that constitute the initial antiviral CTL response. This finding is an important consideration in vaccine design and in the evaluation of vaccine candidates.

KW - Acute Disease

KW - Adult

KW - Amino Acid Sequence

KW - Chronic Disease

KW - Epitopes/genetics

KW - Female

KW - Gene Products, gag/genetics

KW - Genetic Variation

KW - HIV Antigens/genetics

KW - HIV Infections/immunology

KW - HIV-1/genetics

KW - HLA-A2 Antigen

KW - Humans

KW - Male

KW - Middle Aged

KW - T-Lymphocytes, Cytotoxic/immunology

KW - Time Factors

KW - Viral Proteins

KW - gag Gene Products, Human Immunodeficiency Virus

U2 - 10.1084/jem.193.2.181

DO - 10.1084/jem.193.2.181

M3 - SCORING: Journal article

C2 - 11148222

VL - 193

SP - 181

EP - 194

JO - J EXP MED

JF - J EXP MED

SN - 0022-1007

IS - 2

ER -