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Trivalent live attenuated influenza-simian immunodeficiency virus vaccines: efficacy and evolution of cytotoxic T lymphocyte escape in macaques.

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posted on 2013-04-01, 00:00 authored by J Reece, S Alcantara, S Gooneratne, S Jegaskanda, T Amaresena, C Fernandez, K Laurie, A Hurt, S O'Connor, M Harris, J Petravic, A Martyushev, A Grimm, M Davenport, John StambasJohn Stambas, R De Rose, S Kent
There is an urgent need for a human immunodeficiency virus (HIV) vaccine that induces robust mucosal immunity. CD8+ cytotoxic T lymphocytes (CTLs) apply substantial antiviral pressure, but CTLs to individual epitopes select for immune escape variants in both HIV in humans and SIV in macaques. Inducing multiple simian immunodeficiency virus (SIV)-specific CTLs may assist in controlling viremia. We vaccinated 10 Mane-A1*08401+ female pigtail macaques with recombinant influenza viruses expressing three Mane-A1*08401-restricted SIV-specific CTL epitopes and subsequently challenged the animals, along with five controls, intravaginally with SIVmac251. Seroconversion to the influenza virus vector resulted and small, but detectable, SIV-specific CTL responses were induced. There was a boost in CTL responses after challenge but no protection from high-level viremia or CD4 depletion was observed. All three CTL epitopes underwent a coordinated pattern of immune escape during early SIV infection. CTL escape was more rapid in the vaccinees than in the controls at the more dominant CTL epitopes. Although CTL escape can incur a "fitness" cost to the virus, a putative compensatory mutation 20 amino acids upstream from an immunodominant Gag CTL epitope also evolved soon after the primary CTL escape mutation. We conclude that vaccines based only on CTL epitopes will likely be undermined by rapid evolution of both CTL escape and compensatory mutations. More potent and possibly broader immune responses may be required to protect pigtail macaques from SIV.

History

Journal

Journal of virology

Volume

87

Pagination

4146-4160

Location

Washington, D. C.

Open access

  • Yes

ISSN

0022-538X

eISSN

1098-5514

Language

eng

Publication classification

C1 Refereed article in a scholarly journal

Copyright notice

2013, American Society for Microbiology

Issue

8

Publisher

American Society for Microbiology

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