Substantial differences in specificity of HIV-specific cytotoxic T cells in acute and chronic HIV infection - PubMed (original) (raw)

Comparative Study

. 2001 Jan 15;193(2):181-94.

doi: 10.1084/jem.193.2.181.

M A Altfeld, E S Rosenberg, T Nguyen, Y Tang, R L Eldridge, M M Addo, S He, J S Mukherjee, M N Phillips, M Bunce, S A Kalams, R P Sekaly, B D Walker, C Brander

Affiliations

Comparative Study

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

P J Goulder et al. J Exp Med. 2001.

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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Figures

Figure 1

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.

Figure 1

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.

Figure 1

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.

Figure 2

Figure 2

Recognition of SLYNTVATL only in A*0201-positive subjects in chronic infection. Intracellular staining using SL9 and a positive control HIV peptide epitope and A*0201-SL9 tetramer staining of PBMCs from chronically infected subject 9354 (HLA-A*0201/3 B7/35 Cw4/7) and 2 of the 11 A*0201-positive subjects studied in acute infection (expressed as percentage of CD8+ T cells). Controls: percentage of CD8+ T cells showing intracellular IFN-γ staining after incubation with no peptide was, respectively, 0.00% (subject 9354), 0.03% (AC29), and 0.02% (AC13; data not shown). The HIV peptides used as positive controls had previously been established as recognized by these subjects: B7 Gag TL9, TPQDLNTML (p24 Gag); B8 Nef FL8, FLKEKGGL; and B14-gp41-EL9, ERYLKDQQL (reference 50).

Figure 3

Figure 3

(A and B) Recognition of SLYNTVATL and autologous SL9 variant in Elispot assays. (A) Positive control chronic subject 161j, recognition of SL9, and autologous variant SL

F

NTVATL (reference 45). (B) Acute subject AC04: no recognition either of SL9 or autologous SL9 variant. Data from the other 10 A*0201 subjects in acute infection are not shown. SFC, spot-forming cell. (C–H) Recognition of SL9 and SL9 variants that arise most often in HIV infection (>90% of published B clade United States originating sequences; reference 50) using CTL clones derived from PBMCs from chronically infected A*0201-positive subjects.

Figure 3

Figure 3

(A and B) Recognition of SLYNTVATL and autologous SL9 variant in Elispot assays. (A) Positive control chronic subject 161j, recognition of SL9, and autologous variant SL

F

NTVATL (reference 45). (B) Acute subject AC04: no recognition either of SL9 or autologous SL9 variant. Data from the other 10 A*0201 subjects in acute infection are not shown. SFC, spot-forming cell. (C–H) Recognition of SL9 and SL9 variants that arise most often in HIV infection (>90% of published B clade United States originating sequences; reference 50) using CTL clones derived from PBMCs from chronically infected A*0201-positive subjects.

Figure 4

Figure 4

(A and B) Longitudinal study of HIV-specific epitope recognition in subject AC13 (presenting preseroconversion) and subject PI004 (presenting 7–28 wk after seroconversion). Before the onset of HAART in subject 5192d, the viral load had declined from 730,000 HIV-1 RNA copies/ml plasma to 5,000 copies/ml plasma. Subject PI004 did not receive antiretroviral therapy at any time. Peptides that were recognized (references 50 and 76): A2-p17 Gag SL9, SLYNTVATL; A2-gp41 SV10, SLLNATAIAV; B14-p24 Gag DA9, DRFYKTLRA; A2 Vpr, AIIRILQQL; Cw5-Rev SL9 SAEPVPLQL, B14-gp41 ERYLKDQQL; B57-Gag TW10, TSTLQEQIGW; B57-Gag IW9, ISPRTLNAW; B57-Gag KF11, KAFSPEVIPMF; B57-Gag QW9, QASQEVKNW; B8-p24 Gag EI8, EIYKRWII; and B8 Nef FL8, FLKEKGGL. SFC, spot-forming cell.

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