Multispecific Vaccine-Induced Mucosal Cytotoxic T Lymphocytes Reduce Acute-Phase Viral Replication but Fail in Long-Term Control of Simian Immunodeficiency Virus SIVmac239

Thorsten U. Vogel, Matthew R. Reynolds, Deborah H. Fuller, Kathy Vielhuber, Tim Shipley, James T. Fuller, Kevin J. Kunstman, Gerd Sutter, Marta L. Marthas, Volker Erfle, Steven M. Wolinsky, Chenxi Wang, David B. Allison, Erling W. Rud, Nancy Wilson, David Montefiori, John D. Altman, David Watkins

Research output: Contribution to journalArticle

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Abstract

Given the current difficulties generating vaccine-induced neutralizing antibodies to human immunodeficiency virus (HIV), the focus of the vaccine community has shifted toward creating cytotoxic-T-lymphocyte (CTL)-based vaccines. Recent reports of CTL-based vaccine trials in macaques challenged with simian/human immunodeficiency virus SHIV-89.6P have supported the notion that such vaccines can ameliorate the course of disease. However, almost all of these studies included Env as an immunogen and since SHIV-89.6P is sensitive to neutralizing antibodies it is difficult to determine the mechanism(s) of protection. Consequently, SHIV-89.6P challenge of macaques may be a poor model for determining vaccine efficacy in humans. To ascertain the effect of vaccine-induced multispecific mucosal CTL, in the absence of Env-specific antibody, on the control of an immunodeficiency virus challenge, we vaccinated Mamu-A*01+ macaques with constructs encoding a combination of CTL epitopes and full-length proteins (Tat, Rev, and Nef) by using a DNA prime/recombinant modified vaccinia virus Ankara (rMVA) boost regimen. The vaccination induced virus-specific CTL and CD4+ helper T lymphocytes with CTL frequencies as high as 20,000/million peripheral blood mononuclear cells. The final rMVA vaccination, delivered intravenously, engendered long-lived mucosal CTL At 16 weeks after the final rMVA vaccination, the vaccinees and naive, Mamu-A*01+ controls were challenged intrarectally with SIVmac239. Massive early anamnestic cellular immune responses controlled acute-phase viral replication; however, the three vaccinees were unable to control virus replication in the chronic phase. The present study suggests that multispecific mucosal CTL, in the absence of neutralizing antibodies, can achieve a modicum of control over early viral replication but are unable to control chronic-phase viral replication after a high-dose mucosal challenge with a pathogenic simian immunodeficiency virus.

Original languageEnglish
Pages (from-to)13348-13360
Number of pages13
JournalJournal of Virology
Volume77
Issue number24
DOIs
StatePublished - Dec 1 2003
Externally publishedYes

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Simian immunodeficiency virus
Simian Immunodeficiency Virus
cytotoxic T-lymphocytes
Cytotoxic T-Lymphocytes
virus replication
Vaccines
vaccines
Vaccinia virus
Macaca
Neutralizing Antibodies
neutralizing antibodies
Vaccination
vaccination
Human immunodeficiency virus
nef Gene Products
rev Gene Products
HIV
tat Gene Products
Viruses
viruses

ASJC Scopus subject areas

  • Immunology

Cite this

Multispecific Vaccine-Induced Mucosal Cytotoxic T Lymphocytes Reduce Acute-Phase Viral Replication but Fail in Long-Term Control of Simian Immunodeficiency Virus SIVmac239. / Vogel, Thorsten U.; Reynolds, Matthew R.; Fuller, Deborah H.; Vielhuber, Kathy; Shipley, Tim; Fuller, James T.; Kunstman, Kevin J.; Sutter, Gerd; Marthas, Marta L.; Erfle, Volker; Wolinsky, Steven M.; Wang, Chenxi; Allison, David B.; Rud, Erling W.; Wilson, Nancy; Montefiori, David; Altman, John D.; Watkins, David.

In: Journal of Virology, Vol. 77, No. 24, 01.12.2003, p. 13348-13360.

Research output: Contribution to journalArticle

Vogel, TU, Reynolds, MR, Fuller, DH, Vielhuber, K, Shipley, T, Fuller, JT, Kunstman, KJ, Sutter, G, Marthas, ML, Erfle, V, Wolinsky, SM, Wang, C, Allison, DB, Rud, EW, Wilson, N, Montefiori, D, Altman, JD & Watkins, D 2003, 'Multispecific Vaccine-Induced Mucosal Cytotoxic T Lymphocytes Reduce Acute-Phase Viral Replication but Fail in Long-Term Control of Simian Immunodeficiency Virus SIVmac239', Journal of Virology, vol. 77, no. 24, pp. 13348-13360. https://doi.org/10.1128/JVI.77.24.13348-13360.2003
Vogel, Thorsten U. ; Reynolds, Matthew R. ; Fuller, Deborah H. ; Vielhuber, Kathy ; Shipley, Tim ; Fuller, James T. ; Kunstman, Kevin J. ; Sutter, Gerd ; Marthas, Marta L. ; Erfle, Volker ; Wolinsky, Steven M. ; Wang, Chenxi ; Allison, David B. ; Rud, Erling W. ; Wilson, Nancy ; Montefiori, David ; Altman, John D. ; Watkins, David. / Multispecific Vaccine-Induced Mucosal Cytotoxic T Lymphocytes Reduce Acute-Phase Viral Replication but Fail in Long-Term Control of Simian Immunodeficiency Virus SIVmac239. In: Journal of Virology. 2003 ; Vol. 77, No. 24. pp. 13348-13360.
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AU - Reynolds, Matthew R.

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AU - Fuller, James T.

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AU - Erfle, Volker

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AU - Wang, Chenxi

AU - Allison, David B.

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