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

Goulder PJ, Altfeld MA, Rosenberg ES, Nguyen T, Tang Y, Eldridge RL, Addo MM, He S, Mukherjee JS, Phillips MN, Bunce M, Kalams SA, Sekaly RP, Walker BD, Brander C - J. Exp. Med. (2001)

Bottom Line: 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.This finding is an important consideration in vaccine design and in the evaluation of vaccine candidates.

View Article: PubMed Central - PubMed

Affiliation: Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA. goulder@helix.mgh.harvard.edu

ABSTRACT
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.

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(A) Characterization of the HIV-specific CTL responses made in acute HIV infection. The method used is illustrated for subject AC01. Overlapping peptides spanning p17 Gag, p24 Gag, Nef, RT, gp120, gp41, Rev, and Tat were used in Elispot assays, as well as published optimal peptides presented by HLA-A*0201, A3, B35, or Cw4. Examples of positive and negative responses are shown. No responses to Tat or Rev overlapping peptides were observed in this subject (not shown). SFC, spot-forming cell. (B) Proportion of A*0201-positive subjects in acute infection showing a detectable response to the A*0201-SLYNTVATL epitope. (C) Proportion of A*0201-positive subjects in chronic infection showing a detectable response to the A*0201-SLYNTVATL epitope, using data from four published studies. Criteria for inclusion of a published study were: demonstration of specificity of A*0201-SL9 response by cytotoxicity assays or peptide–MHC tetramers, and more than 1 subject studied.
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Figure 1: (A) Characterization of the HIV-specific CTL responses made in acute HIV infection. The method used is illustrated for subject AC01. Overlapping peptides spanning p17 Gag, p24 Gag, Nef, RT, gp120, gp41, Rev, and Tat were used in Elispot assays, as well as published optimal peptides presented by HLA-A*0201, A3, B35, or Cw4. Examples of positive and negative responses are shown. No responses to Tat or Rev overlapping peptides were observed in this subject (not shown). SFC, spot-forming cell. (B) Proportion of A*0201-positive subjects in acute infection showing a detectable response to the A*0201-SLYNTVATL epitope. (C) Proportion of A*0201-positive subjects in chronic infection showing a detectable response to the A*0201-SLYNTVATL epitope, using data from four published studies. Criteria for inclusion of a published study were: demonstration of specificity of A*0201-SL9 response by cytotoxicity assays or peptide–MHC tetramers, and more than 1 subject studied.

Mentions: To characterize the HIV-specific CTL response in acute infection for each subject enrolled, IFN-γ responses to epitopes within p17 Gag, p24 Gag, Nef, RT, gp41, gp120, Tat, and Rev were screened in Elispot assays using panels of overlapping 15–20-mer peptides that overlapped by 10 amino acids to span each protein. The approach that was used is illustrated for one subject in Fig. 1 A. In addition, individual peptides previously defined as optimal epitopes corresponding to the HLA class I alleles expressed by each subject were tested for recognition. Thus, for each of the 11 A*0201-positive subjects studied with early HIV infection, 290 overlapping 15–20-mer peptides and between 11 and 29 (median of 24) optimal epitope peptides were used to characterize the CTL response. Overall, 78 different optimal epitope peptides were used in the studies of 11 A*0201-positive subjects with early infection.


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

Goulder PJ, Altfeld MA, Rosenberg ES, Nguyen T, Tang Y, Eldridge RL, Addo MM, He S, Mukherjee JS, Phillips MN, Bunce M, Kalams SA, Sekaly RP, Walker BD, Brander C - J. Exp. Med. (2001)

(A) Characterization of the HIV-specific CTL responses made in acute HIV infection. The method used is illustrated for subject AC01. Overlapping peptides spanning p17 Gag, p24 Gag, Nef, RT, gp120, gp41, Rev, and Tat were used in Elispot assays, as well as published optimal peptides presented by HLA-A*0201, A3, B35, or Cw4. Examples of positive and negative responses are shown. No responses to Tat or Rev overlapping peptides were observed in this subject (not shown). SFC, spot-forming cell. (B) Proportion of A*0201-positive subjects in acute infection showing a detectable response to the A*0201-SLYNTVATL epitope. (C) Proportion of A*0201-positive subjects in chronic infection showing a detectable response to the A*0201-SLYNTVATL epitope, using data from four published studies. Criteria for inclusion of a published study were: demonstration of specificity of A*0201-SL9 response by cytotoxicity assays or peptide–MHC tetramers, and more than 1 subject studied.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193346&req=5

Figure 1: (A) Characterization of the HIV-specific CTL responses made in acute HIV infection. The method used is illustrated for subject AC01. Overlapping peptides spanning p17 Gag, p24 Gag, Nef, RT, gp120, gp41, Rev, and Tat were used in Elispot assays, as well as published optimal peptides presented by HLA-A*0201, A3, B35, or Cw4. Examples of positive and negative responses are shown. No responses to Tat or Rev overlapping peptides were observed in this subject (not shown). SFC, spot-forming cell. (B) Proportion of A*0201-positive subjects in acute infection showing a detectable response to the A*0201-SLYNTVATL epitope. (C) Proportion of A*0201-positive subjects in chronic infection showing a detectable response to the A*0201-SLYNTVATL epitope, using data from four published studies. Criteria for inclusion of a published study were: demonstration of specificity of A*0201-SL9 response by cytotoxicity assays or peptide–MHC tetramers, and more than 1 subject studied.
Mentions: To characterize the HIV-specific CTL response in acute infection for each subject enrolled, IFN-γ responses to epitopes within p17 Gag, p24 Gag, Nef, RT, gp41, gp120, Tat, and Rev were screened in Elispot assays using panels of overlapping 15–20-mer peptides that overlapped by 10 amino acids to span each protein. The approach that was used is illustrated for one subject in Fig. 1 A. In addition, individual peptides previously defined as optimal epitopes corresponding to the HLA class I alleles expressed by each subject were tested for recognition. Thus, for each of the 11 A*0201-positive subjects studied with early HIV infection, 290 overlapping 15–20-mer peptides and between 11 and 29 (median of 24) optimal epitope peptides were used to characterize the CTL response. Overall, 78 different optimal epitope peptides were used in the studies of 11 A*0201-positive subjects with early infection.

Bottom Line: 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.This finding is an important consideration in vaccine design and in the evaluation of vaccine candidates.

View Article: PubMed Central - PubMed

Affiliation: Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA. goulder@helix.mgh.harvard.edu

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus