Reversion of CTL escape-variant immunodeficiency viruses in vivo

Thomas C. Friedrich; Elizabeth J. Dodds; Levi J. Yant; Lara Vojnov; Richard Rudersdorf; Candice Cullen; David T. Evans; Ronald C. Desrosiers; Bianca R. Mothé; John Sidney; Alessandro Sette; Kevin Kunstman; Steven Wolinsky; Michael Piatak; Jeffrey Lifson; Austin L. Hughes; Nancy Wilson; David H. O'Connor; David I. Watkins

doi:10.1038/nm998

Reversion of CTL escape-variant immunodeficiency viruses in vivo

Thomas C. Friedrich, Elizabeth J. Dodds, Levi J. Yant, Lara Vojnov, Richard Rudersdorf, Candice Cullen, David T. Evans, Ronald C. Desrosiers, Bianca R. Mothé, John Sidney, Alessandro Sette, Kevin Kunstman, Steven Wolinsky, Michael Piatak, Jeffrey Lifson, Austin L. Hughes, Nancy Wilson, David H. O'Connor, David I. Watkins^*

^*Corresponding author for this work

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

330 Scopus citations

Abstract

Engendering cytotoxic T-lymphocyte (CTL) responses is likely to be an important goal of HIV vaccines. However, CTLs select for viral variants that escape immune detection. Maintenance of such escape variants in human populations could pose an obstacle to HIV vaccine development. We first observed that escape mutations in a heterogeneous simian immunodeficiency virus (SIV) isolate were lost upon passage to new animals. We therefore infected macaques with a cloned SIV bearing escape mutations in three immunodominant CTL epitopes, and followed viral evolution after infection. Here we show that each mutant epitope sequence continued to evolve in vivo, often re-establishing the original, CTL-susceptible sequence. We conclude that escape from CTL responses may exact a cost to viral fitness. In the absence of selective pressure upon transmission to new hosts, these original escape mutations can be lost. This suggests that some HIV CTL epitopes will be maintained in human populations.

Original language	English (US)
Pages (from-to)	275-281
Number of pages	7
Journal	Nature Medicine
Volume	10
Issue number	3
DOIs	https://doi.org/10.1038/nm998
State	Published - Mar 2004

Funding

We gratefully acknowledge J. Helgeland, J. Mitchen, C. Bunger, K. Vielhuber and E. Rakasz; I. Bolton and the veterinarians and technicians of the WNPRC; and T. Jacoby and W. Rehrauer for their work in support of this study. We also thank W. Rehrauer for critical review of this manuscript. This work was supported by National Institutes of Health grants RO1-AI-46366, RO1-AI-49120 and RO1-AI-52056 to D.I.W., and P51 RR001676-43 to the WNPRC. D.I.W. is an Elizabeth Glaser Scientist. A.S. is supported by NIH-NIAID contract NO1-AI-95362.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nm998

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Friedrich, T. C., Dodds, E. J., Yant, L. J., Vojnov, L., Rudersdorf, R., Cullen, C., Evans, D. T., Desrosiers, R. C., Mothé, B. R., Sidney, J., Sette, A., Kunstman, K., Wolinsky, S., Piatak, M., Lifson, J., Hughes, A. L., Wilson, N., O'Connor, D. H., & Watkins, D. I. (2004). Reversion of CTL escape-variant immunodeficiency viruses in vivo. Nature Medicine, 10(3), 275-281. https://doi.org/10.1038/nm998

@article{87fa003e00474aff800187b3d389a09b,

title = "Reversion of CTL escape-variant immunodeficiency viruses in vivo",

abstract = "Engendering cytotoxic T-lymphocyte (CTL) responses is likely to be an important goal of HIV vaccines. However, CTLs select for viral variants that escape immune detection. Maintenance of such escape variants in human populations could pose an obstacle to HIV vaccine development. We first observed that escape mutations in a heterogeneous simian immunodeficiency virus (SIV) isolate were lost upon passage to new animals. We therefore infected macaques with a cloned SIV bearing escape mutations in three immunodominant CTL epitopes, and followed viral evolution after infection. Here we show that each mutant epitope sequence continued to evolve in vivo, often re-establishing the original, CTL-susceptible sequence. We conclude that escape from CTL responses may exact a cost to viral fitness. In the absence of selective pressure upon transmission to new hosts, these original escape mutations can be lost. This suggests that some HIV CTL epitopes will be maintained in human populations.",

author = "Friedrich, {Thomas C.} and Dodds, {Elizabeth J.} and Yant, {Levi J.} and Lara Vojnov and Richard Rudersdorf and Candice Cullen and Evans, {David T.} and Desrosiers, {Ronald C.} and Moth{\'e}, {Bianca R.} and John Sidney and Alessandro Sette and Kevin Kunstman and Steven Wolinsky and Michael Piatak and Jeffrey Lifson and Hughes, {Austin L.} and Nancy Wilson and O'Connor, {David H.} and Watkins, {David I.}",

note = "Funding Information: We gratefully acknowledge J. Helgeland, J. Mitchen, C. Bunger, K. Vielhuber and E. Rakasz; I. Bolton and the veterinarians and technicians of the WNPRC; and T. Jacoby and W. Rehrauer for their work in support of this study. We also thank W. Rehrauer for critical review of this manuscript. This work was supported by National Institutes of Health grants RO1-AI-46366, RO1-AI-49120 and RO1-AI-52056 to D.I.W., and P51 RR001676-43 to the WNPRC. D.I.W. is an Elizabeth Glaser Scientist. A.S. is supported by NIH-NIAID contract NO1-AI-95362.",

year = "2004",

month = mar,

doi = "10.1038/nm998",

language = "English (US)",

volume = "10",

pages = "275--281",

journal = "Nature Medicine",

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Friedrich, TC, Dodds, EJ, Yant, LJ, Vojnov, L, Rudersdorf, R, Cullen, C, Evans, DT, Desrosiers, RC, Mothé, BR, Sidney, J, Sette, A, Kunstman, K, Wolinsky, S, Piatak, M, Lifson, J, Hughes, AL, Wilson, N, O'Connor, DH & Watkins, DI 2004, 'Reversion of CTL escape-variant immunodeficiency viruses in vivo', Nature Medicine, vol. 10, no. 3, pp. 275-281. https://doi.org/10.1038/nm998

TY - JOUR

T1 - Reversion of CTL escape-variant immunodeficiency viruses in vivo

AU - Friedrich, Thomas C.

AU - Dodds, Elizabeth J.

AU - Yant, Levi J.

AU - Vojnov, Lara

AU - Rudersdorf, Richard

AU - Cullen, Candice

AU - Evans, David T.

AU - Desrosiers, Ronald C.

AU - Mothé, Bianca R.

AU - Sidney, John

AU - Sette, Alessandro

AU - Kunstman, Kevin

AU - Wolinsky, Steven

AU - Piatak, Michael

AU - Lifson, Jeffrey

AU - Hughes, Austin L.

AU - Wilson, Nancy

AU - O'Connor, David H.

AU - Watkins, David I.

N1 - Funding Information: We gratefully acknowledge J. Helgeland, J. Mitchen, C. Bunger, K. Vielhuber and E. Rakasz; I. Bolton and the veterinarians and technicians of the WNPRC; and T. Jacoby and W. Rehrauer for their work in support of this study. We also thank W. Rehrauer for critical review of this manuscript. This work was supported by National Institutes of Health grants RO1-AI-46366, RO1-AI-49120 and RO1-AI-52056 to D.I.W., and P51 RR001676-43 to the WNPRC. D.I.W. is an Elizabeth Glaser Scientist. A.S. is supported by NIH-NIAID contract NO1-AI-95362.

PY - 2004/3

Y1 - 2004/3

N2 - Engendering cytotoxic T-lymphocyte (CTL) responses is likely to be an important goal of HIV vaccines. However, CTLs select for viral variants that escape immune detection. Maintenance of such escape variants in human populations could pose an obstacle to HIV vaccine development. We first observed that escape mutations in a heterogeneous simian immunodeficiency virus (SIV) isolate were lost upon passage to new animals. We therefore infected macaques with a cloned SIV bearing escape mutations in three immunodominant CTL epitopes, and followed viral evolution after infection. Here we show that each mutant epitope sequence continued to evolve in vivo, often re-establishing the original, CTL-susceptible sequence. We conclude that escape from CTL responses may exact a cost to viral fitness. In the absence of selective pressure upon transmission to new hosts, these original escape mutations can be lost. This suggests that some HIV CTL epitopes will be maintained in human populations.

AB - Engendering cytotoxic T-lymphocyte (CTL) responses is likely to be an important goal of HIV vaccines. However, CTLs select for viral variants that escape immune detection. Maintenance of such escape variants in human populations could pose an obstacle to HIV vaccine development. We first observed that escape mutations in a heterogeneous simian immunodeficiency virus (SIV) isolate were lost upon passage to new animals. We therefore infected macaques with a cloned SIV bearing escape mutations in three immunodominant CTL epitopes, and followed viral evolution after infection. Here we show that each mutant epitope sequence continued to evolve in vivo, often re-establishing the original, CTL-susceptible sequence. We conclude that escape from CTL responses may exact a cost to viral fitness. In the absence of selective pressure upon transmission to new hosts, these original escape mutations can be lost. This suggests that some HIV CTL epitopes will be maintained in human populations.

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DO - 10.1038/nm998

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JO - Nature Medicine

JF - Nature Medicine

IS - 3

ER -

Reversion of CTL escape-variant immunodeficiency viruses in vivo

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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