Escape in One of Two Cytotoxic T-Lymphocyte Epitopes Bound by a High-Frequency Major Histocompatibility Complex Class I Molecule, Mamu-A*02: a Paradigm for Virus Evolution and Persistence?

Vogel, Thorsten U.; Friedrich, Thomas C.; O’Connor, David H.; Rehrauer, William M.; Dodds, Elizabeth; Hickman, Heather D.; Hildebrand, William H.; Sidney, John; Sette, Alessandro; Hughes, Austin L.; Horton, Helen; Vielhuber, Kathy; Rudersdorf, Richard; Souza, Ivna P. de; Reynolds, Matthew R.; Allen, Todd M.; Wilson, Nancy A.; Watkins, David I.

doi:10.1128/jvi.76.22.11623-11636.2002

Cited by 76 publications

(115 citation statements)

References 37 publications

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“…Natural CTL responses were defined as HIVspecific CTL responses occurring in naïve macaques or macaques vaccinated against a different protein. A comprehensive metaanalysis of all documented CTL escape events was performed; in total, 35 CTL escape variants were analyzed (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Of these, 18 represented escape from a natural CTL response (12 occurred in naïve macaques, 6 in macaques vaccinated against a protein other than the one in which escape occurred) and 17 represented escape from a vaccine-induced memory CTL response.…”

Section: Resultsmentioning

confidence: 99%

In vivoCD8⁺T cell control of immunodeficiency virus infection in humans and macaques

Asquith

McLean

2007

Proc. Natl. Acad. Sci. U.S.A.

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Forty million people are estimated to be infected with HIV-1, and only a small fraction of those have access to life-prolonging antiretroviral treatment. As the epidemic grows there is an urgent need for effective therapeutic and prophylactic vaccines. Nonhuman primate models of immunodeficiency virus infection are essential for the preclinical evaluation of candidate vaccines. To interpret the results of these trials, comparative studies of the human and macaque immune responses are needed. Despite the widespread use of macaques to evaluate vaccines designed to elicit a CD8 ؉ cytotoxic T lymphocyte (CTL) response, the efficiency with which CTL control immunodeficiency virus infections has not been compared between humans and macaques, largely because of difficulties in assaying the functional CTL response. We recently developed a method for estimating the rate at which CTLs kill cells productively infected with HIV-1 in humans in vivo. Here, using the same technique, we quantify the rate at which CTLs kill infected cells in macaque models of HIV infection. We show that CTLs kill productively infected cells significantly faster (P ‫؍‬ 0.004) and that escape variants have significantly higher fitness costs (P ‫؍‬ 0.003) in macaques compared with humans. These results suggest that it may be easier to elicit a protective CTL response in macaques than in humans and that vaccine studies conducted in macaques need to be interpreted accordingly.human immunodeficiency virus ͉ simian immunodeficiency virus ͉ cytotoxic T lymphocyte ͉ vaccine ͉ viral escape S imian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) infection of nonhuman primates, notably rhesus macaques (Macaca mulatta) and pigtail macaques (Macaca nemestrina), reproduce many of the key elements of HIV infection of humans, including CD4 ϩ cell depletion and an AIDS-like syndrome. Importantly, for appraising vaccine efficacy, macaques and humans have similar immune systems (1). However, it has been difficult to compare immune control of immunodeficiency viruses in humans and macaques. A number of commonly used SHIV strains (SHIV-89.6P, SHIV-DH12R, and SHIV-KU) are more susceptible to antibody neutralization than HIV-1, and it has therefore been suggested that they are poor systems for testing vaccines designed to elicit an antibody response (2). The efficiency with which CD8 ϩ cytotoxic T lymphocytes (CTLs) control immunodeficiency virus infections has not been compared between humans and macaques, largely because of difficulties in assaying the functional CTL response (3). A method for quantifying CTL lytic function in vivo (4, 5) now makes this comparison possible. ResultsThe rate at which a CTL escape variant grows out and replaces the wild-type (WT) strain, ''the rate of escape,'' is determined by the balance between the rate of CTL killing evaded by the escape variant and the fitness cost of the variant (see Methods). By quantifying the rate of escape and the fitness cost of known CTL escape variants the rate of killing of prod...

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Section: Resultsmentioning

confidence: 99%

In vivoCD8⁺T cell control of immunodeficiency virus infection in humans and macaques

Asquith

McLean

2007

Proc. Natl. Acad. Sci. U.S.A.

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“…A similar breadth of response to Gag is found in Mamu-A*01-expressing monkeys infected with SIV, with a dominant response directed toward the CM9 Gag 181-189 epitope (37) and minor responses directed against three other epitopes of Gag, identified based on class I-binding motifs (38). In Mamu-A*02-expressing monkeys vaccinated with a DNA/ modified vaccinia virus Ankara regimen and subsequently infected with SIVmac239, cytotoxic T cell responses to Gag appear to be restricted to a single epitope in p17 (Gag 71-79 GY9) (39). Interestingly, in the two monkeys that expressed this class I allele in our study (M2001 and M1699), there was no evidence of a p17-specific response (peptides , and instead robust responses to at least two regions within p27 were induced based on pooled peptide assays.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-Transduced Dendritic Cells Injected into Skin or Lymph Node Prime Potent Simian Immunodeficiency Virus-Specific T Cell Immunity in Monkeys

Brown¹,

Gao²,

Alber³

et al. 2003

The Journal of Immunology

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Adenoviral vectors can be used to deliver complex Ag to dendritic cells (DC), and thus may be ideal for stimulating broad T cell responses to viral pathogens and tumors. To test this hypothesis in a relevant primate model, we used recombinant adenovirus serotype 5 vectors expressing SIV Gag Ag to transduce monocyte-derived DC from rhesus macaques, and then immunized donor animals either by intradermal or intranodal injections. T cell responses were evaluated by ELISPOT assay using previously frozen PBMC pulsed with pools of 15-mer peptides representing the Gag sequence. Immunization resulted in rapid and potent induction of T cell responses to multiple regions of Gag, with frequencies approaching 1 Gag-specific T cell per 500 uncultured PBMC. Surprisingly, intradermal and intranodal injections generated a similar intensity and breadth of response, indicating that administration of Ag-expressing DC by either route may be equally effective at inducing immune responses. Detailed analysis of two monkeys revealed CD8+ T cell responses to several peptide epitopes of Gag not previously described, at least two of which are restricted by MHC class I alleles not currently identified. Repeated vaccination did not induce T cell responses to the adenoviral vector and did not prevent Ag-expressing DC injected under the capsule of the lymph node from migrating to the paracortex and interposing between T cells. However, boost injections of adenovirus-transduced DC were generally limited in efficacy. These findings support the use of adenovirus-transduced DC in the therapy of HIV infection and cancer.

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“…These mutations certainly could affect epitope peptide processing and presentation. In the Mamu-A*01 Ϫ Mamu-A*02 ϩ monkeys, 78 -100% of the virus in each monkey had mutations in the Nef p199RY epitope (96% overall), and 26% of those mutations were in the residues of the peptide that are most important for binding to Mamu-A*02 (positions 2 and 9) (35,36). In the Mamu-A*01…”

Section: Fewer Mutations In the Nef P199ry Epitope Are Found In Mamu-mentioning

confidence: 99%

Immunodomination in the Evolution of Dominant Epitope-Specific CD8+ T Lymphocyte Responses in Simian Immunodeficiency Virus-Infected Rhesus Monkeys

Newberg

McEvers

Gorgone

et al. 2006

The Journal of Immunology

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Because the control of HIV-1 replication is largely dependent on CD8+ T lymphocyte responses specific for immunodominant viral epitopes, vaccine strategies that increase the breadth of dominant epitope-specific responses should contribute to containing HIV-1 spread. Developing strategies to elicit such broad immune responses will require an understanding of the mechanisms responsible for focusing CD8+ T lymphocyte recognition on a limited number of epitopes. To explore this biology, we identified cohorts of rhesus monkeys that expressed the MHC class I molecules Mamu-A*01, Mamu-A*02, or both, and assessed the evolution of their dominant epitope-specific CD8+ T lymphocyte responses (Gag p11C- and Tat TL8-specific in the Mamu-A*01+ and Nef p199RY-specific in the Mamu-A*02+ monkeys) following acute SIV infection. The Mamu-A*02+ monkeys that also expressed Mamu-A*01 exhibited a significant delay in the evolution of the CD8+ T lymphocyte responses specific for the dominant Mamu-A*02-restricted SIV epitope, Nef p199RY. This delay in kinetics was not due to differences in viral load kinetics or magnitude or in viral escape mutations, but was associated with the evolution of the Mamu-A*01-restricted CD8+ T lymphocyte responses to the highly dominant SIV epitopes Gag p11C and Tat TL8. Thus, the evolution of dominant epitope-specific CD8+ T lymphocyte responses can be suppressed by other dominant epitope-specific responses, and this immunodomination is important in determining the kinetics of dominant epitope-specific responses.

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Escape in One of Two Cytotoxic T-Lymphocyte Epitopes Bound by a High-Frequency Major Histocompatibility Complex Class I Molecule, Mamu-A*02: a Paradigm for Virus Evolution and Persistence?

Cited by 76 publications

References 37 publications

In vivoCD8⁺T cell control of immunodeficiency virus infection in humans and macaques

In vivoCD8⁺T cell control of immunodeficiency virus infection in humans and macaques

Adenovirus-Transduced Dendritic Cells Injected into Skin or Lymph Node Prime Potent Simian Immunodeficiency Virus-Specific T Cell Immunity in Monkeys

Immunodomination in the Evolution of Dominant Epitope-Specific CD8+ T Lymphocyte Responses in Simian Immunodeficiency Virus-Infected Rhesus Monkeys

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Escape in One of Two Cytotoxic T-Lymphocyte Epitopes Bound by a High-Frequency Major Histocompatibility Complex Class I Molecule, Mamu-A*02: a Paradigm for Virus Evolution and Persistence?

Cited by 76 publications

References 37 publications

In vivoCD8+T cell control of immunodeficiency virus infection in humans and macaques

In vivoCD8+T cell control of immunodeficiency virus infection in humans and macaques

Adenovirus-Transduced Dendritic Cells Injected into Skin or Lymph Node Prime Potent Simian Immunodeficiency Virus-Specific T Cell Immunity in Monkeys

Immunodomination in the Evolution of Dominant Epitope-Specific CD8+ T Lymphocyte Responses in Simian Immunodeficiency Virus-Infected Rhesus Monkeys

Contact Info

Product

Resources

About

In vivoCD8⁺T cell control of immunodeficiency virus infection in humans and macaques

In vivoCD8⁺T cell control of immunodeficiency virus infection in humans and macaques