Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia

Abstract

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections are characterized by early peaks of viraemia that decline as strong cellular immune responses develop1,2. Although it has been shown that virus-specific CD8-positive cytotoxic T lymphocytes (CTLs) exert selective pressure during HIV and SIV infection3,4,5,6,7,8,9,10,11, the data have been controversial12,13. Here we show that Tat-specific CD8-positive T-lymphocyte responses select for new viral escape variants during the acute phase of infection. We sequenced the entire virus immediately after the acute phase, and found that amino-acid replacements accumulated primarily in Tat CTL epitopes. This implies that Tat-specific CTLs may be significantly involved in controlling wild-type virus replication, and suggests that responses against viral proteins that are expressed early during the viral life cycle might be attractive targets for HIV vaccine development.

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Figure 1: Quantitation of CD8-positive T-lymphocyte responses to various Mamu-A*01-bound peptides.
Figure 2: Variation is present in the SL8 epitope of all 10 Mamu-A*01-positive animals after acute SIV infection using analysis of clones isolated from plasma virus.
Figure 3: CTL analyses of CD8-positive T-lymphocytes stimulated with the SL8 peptide.
Figure 4: Inverse correlation between plasma viral concentrations and peak dN in Tat.

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Acknowledgements

We thank L. Smith and B. Becker for preparation of this manuscript and C. D. Pauza and the Immunology and Virology Core Laboratory for infection with molecularly cloned SIVMAC239 nef stop and monitoring of macaques. This work was supported by the NIAID, NCRR and the The James B. Pendleton Charitable Trust. D.I.W. is an Elizabeth Glaser scientist.

Author information

Correspondence to David I. Watkins.

Supplementary information

Figure legends and table 1 (DOC 158 kb)

Figure legends and table 1 (DOC 158 kb)

Figure legends and table 1 (DOC 158 kb)

Figure legends and table 1 (DOC 158 kb)

Figure legends and table 1 (DOC 158 kb)

Figure legends and table 1 (DOC 158 kb)

Figure legends and table 1 (DOC 158 kb)

Figure legends and table 1 (DOC 158 kb)

Figure legends and table 1 (DOC 158 kb)

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