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HIV and SIV CTL escape: implications for vaccine design

Nature Reviews Immunology volume 4, pages 630–640 (2004)Cite this article

Key Points

  • CD8+ T cells (broadly, cytotoxic T lymphocytes, CTLs) have an important role in the control of immunodeficiency virus infection.

  • CTL escape is an important mechanism by which the virus evades the immune response.

  • The occurrence and timing of escape depends on a variety of factors. Similarly, the significance of escape for the patient and for viral evolution is variable, ranging from precipitation to AIDS at one extreme, to successful suppression of viraemia following escape at the other extreme.

  • CTL escape mutations that are most probably of relevance to natural or vaccine-induced immune-mediated control of viraemia are those that occur at a considerable fitness cost to the virus: that is, those that reduce viral replicative capacity. Recent examples of escape followed by immune control of HIV and simian immunodeficiency virus (SIV) are discussed.

  • The consequences for the evolution of HIV of the transmission of viruses that encode escape mutations depend on the fitness cost of the mutation: mutations that result in significantly reduced replication capacity of the virus revert to wild-type following transmission to an HLA-mismatched recipient, whereas mutations that incur little fitness cost probably persist.

  • Mechanisms of mutational escape, including recently described processing mutations, are discussed.

  • CTL escape has implications for vaccine design. The detailed understanding of qualitative differences between CTLs is crucial to determine which epitopes need to be included in a vaccine and which need to be excluded.

Abstract

Cytotoxic T lymphocytes (CTLs) have a central role in the successful control of immunodeficiency virus infection. Evasion of this immune response through CTL escape is therefore an important factor in HIV and simian immunodeficiency virus pathogenesis. During the course of an infection, the precise timing of the occurrence of escape mutations and their location in the viral genome can indicate the efficacy of certain CTL specificities and the cost to viral fitness of particular escape mutations — factors that are highly relevant to vaccine design. Also crucial for vaccine design is the extent to which CTL escape is driving the evolution of HIV at the population level. Here, we highlight the important lessons that can be learned from immunodeficiency virus CTL escape.

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Figure 1: The natural history of SIV infection.
Figure 2: Evolution of viral escape variants in Mamu-A*01-positive Indian macaques infected with SIV.
Figure 3: Pattern of the timing of HIV CTL escape in relation to emergence of different HLA-B57- and HLA-A2-restricted CTL specificities.
Figure 4: Efficacy of CTL activity and viral cost of escape.
Figure 5: The dynamic balance between the factors that contribute to the occurrence of escape.
Figure 6: Mechanisms of mutational escape in HIV and SIV.

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Acknowledgements

We thank D. O'Connor and T. Friedrich for constructive criticism of this manuscript. This work was supported by the Wellcome Trust (P.J.R.G.), the National Institutes of Health and the Doris Duke Charitable Foundation. P.J.R.G. and D.I.W. are Elizabeth Glaser Scientists.

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Authors and Affiliations

  1. Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, OX1 3SY, UK

    Philip J. R. Goulder

  2. Partners AIDS Research Center and Harvard Medical School, Boston, 02129, Massachusetts, USA

    Philip J. R. Goulder

  3. Wisconsin National Primate Research Center, Madison, 53715, Wisconsin, USA

    David I. Watkins

  4. Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, Madison, 53706, Wisconsin, USA

    David I. Watkins

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DATABASES

Entrez Gene

CD4

CD8

Env

ERAAP

gag

HLA-A

HLA-B

HLA-C

Nef

Rev

TAP

tat

Vpr

Infectious Disease Information

HIV

Glossary

LONG-TERM NON-PROGRESSION

(LTNP). There is no universally adopted definition of LTNP, and often LTNP is used interchangeably with HIV controller, because control of viraemia is strongly predictive of LTNP. So, loosely, LTNP refers to HIV-infected individuals whose plasma viral load is less than 1,000 HIV RNA copies per ml. Stricter definitions of LTNP include the duration of infection and the number of CD4+ T cells.

PURIFYING SELECTION

Selection pressure that favours conservation of amino-acid sequence.

VIRAL FITNESS

Viral fitness is context specific, and it refers to the relative ability of a virus to replicate under particular conditions, such as those that occur when the immune response or antiretroviral therapy is acting on the virus. Viral fitness is only increased as a result of selection of escape mutants.

ANCHOR POSITION

Amino-acid residues of an antigenic peptide that bind in pockets in the peptide-binding groove of a MHC molecule. They account for much of the binding energy and specificity of binding.

REPLICATIVE CAPACITY

Replicative (or replication) capacity is an absolute measure of the ability of the virus to replicate under standard conditions, such as in an in vitro-assay system that compares, for example, the virus under study with a laboratory-adapted strain (such as NL4-3). Replicative capacity can be reduced by mutations that increase viral fitness.

ELISPOT

An antibody-capture-based method for enumerating specific T cells (CD4+ and CD8+) that secrete a particular cytokine (often interferon-γ).

TETRAMER STAINING

Biotinylated monomeric MHC molecules are folded in vitro together with a specific peptide that binds in the binding groove. These peptide–MHC complexes are then tetramerized using a fluorescently labelled streptavidin molecule. The tetramers bind T cells that express T-cell receptors specific for the cognate peptide–MHC complex. They can therefore be used to track antigen-specific T cells by flow cytometry.

SIMIAN–HUMAN IMMUNODEFICIENCY VIRUS

(SHIV). SHIVs are chimeric viruses that are created by inserting the envelope protein (Env), the transcriptional transactivator (Tat) and the regulator of virion gene expression (Rev) of HIV into the SIVMAC239 clone. Depending on the particular HIV Env protein, these SHIVs have different in vivo characteristics. The SHIV chimeric viruses are best used for testing antibodies specific for HIV in non-human primate models.

ORIGINAL ANTIGENIC SIN

A 'footprint' of immune responses is established during the first exposure to a virus, and the same specific memory T-cell populations are preferentially re-expanded when re-exposed to the same antigen, thereby limiting the clonal expansion of new specific T cells. A similar mechanism has been proposed for B-cell responses.

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Goulder, P., Watkins, D. HIV and SIV CTL escape: implications for vaccine design. Nat Rev Immunol 4, 630–640 (2004). https://doi.org/10.1038/nri1417

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