Viral Escape from Dominant Simian Immunodeficiency Virus Epitope-Specific Cytotoxic T Lymphocytes in DNA-Vaccinated Rhesus Monkeys

Barouch, Dan H.; Kunstman, Jennifer; Glowczwskie, Jennifer; Kunstman, Kevin; Egan, Michael A.; Peyerl, Fred W.; Santra, Sampa; Kuroda, Marcelo J.; Schmitz, Jörn E.; Beaudry, Kristin; Krivulka, Georgia R.; Lifton, Michelle A.; Gorgone, Darci A.; Wolinsky, Steven M.; Letvin, Norman L.

doi:10.1128/jvi.77.13.7367-7375.2003

Cited by 153 publications

(132 citation statements)

References 32 publications

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“…Whether the failure of prophylactic vaccination is due to the evolution of immune escape mutations during acute infection has been discussed (10,11,63). Although immune escape is rampant and is an important hurdle for HIV vaccine development (37), it is an insufficient explanation for the failure of the vaccinations discussed here (63).…”

Section: Discussionmentioning

confidence: 99%

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Boer

2007

J Virol

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Although CD8 ؉ T cells play an important role in controlling viral infections, boosting specific CD8 ؉ T cells by prophylactic vaccination with simian immunodeficiency virus (SIV) epitopes fails to provide sterilizing immunity. Viral replication rates and viral contraction rates after the peak viremia hardly depend on the presence of memory CD8 ؉ T cells. To study these paradoxical findings, we parameterize novel mathematical models for acute SIV and human immunodeficiency virus infection. These models explain that failure of vaccination is due to the fact that effector/target ratios are too low during the viral expansion phase. Because CD8 ؉ T cells require cell-to-cell contacts, immune protection requires high effector/target ratios at the primary site of infection. Effector/target ratios become favorable for immune control at the time of the peak in the viral load when the virus becomes limited by other factors, such as the availability of uninfected target cells. At the viral set point, effector/target ratios are much higher, and perturbations of the number of CD8 ؉ effector cells have a large impact on the viral load. Such protective effector/target ratios are difficult to achieve with nucleic acid-or protein-based vaccines.

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Section: Discussionmentioning

confidence: 99%

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Boer

2007

J Virol

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“…Importantly, the rate and frequency of viral escape from CTL can differ for different viral isolates. Barouch et al recently showed that seven of nine Mamu-A * 01 ϩ rhesus monkeys infected with SIVsmE660 demonstrated viral escape at both the Env TL9 and the Gag p11C, C-M epitopes (2). In contrast, only 1 of 15 Mamu-A * 01 ϩ rhesus monkeys infected with SHIV-89.6P demonstrated viral escape from p11C, C-M-specific CTL (3).…”

Section: Discussionmentioning

confidence: 99%

“…In Mamu-A * 01 ϩ rhesus monkeys, mutation at the Tat SL8 epitope predictably occurs during primary infection with SIVmac239 (1), but escape at the Env TL9 and Gag p11C, C-M epitopes occurs more slowly (2,3,8). Importantly, the rate and frequency of viral escape from CTL can differ for different viral isolates.…”

Section: Discussionmentioning

confidence: 99%

“…This selection pressure is so great that a dominant Tat epitope universally mutated away from CTL recognition during the period of primary SIVmac239 infection in Mamu-A * 01 ϩ rhesus monkeys (1). Moreover, mutations in dominant Gag and Env epitopes occurred in seven of nine Mamu-A * 01 ϩ rhesus monkeys following SIVsmE660 challenge during the assessment of a DNA vaccine strategy (2). In fact, regions of HIV type 1 (HIV-1) hypervariability have been shown to be associated with specific CTL epitopes in humans with particular major histocompatibility complex class I haplotypes (24).…”

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confidence: 99%

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Simian-Human Immunodeficiency Virus Escape from Cytotoxic T-Lymphocyte Recognition at a Structurally Constrained Epitope

Peyerl

Barouch

Yeh

et al. 2003

J Virol

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Virus-specific cytotoxic T lymphocytes (CTL) exert intense selection pressure on replicating simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) in infected individuals. The immunodominant Mamu-A * 01-restricted Gag p11C, C-M epitope is highly conserved among all sequenced isolates of SIV and therefore likely is structurally constrained. The strategies used by virus isolates to mutate away from an immunodominant epitope-specific CTL response are not well defined. Here we demonstrate that the emergence of a position 2 p11C, C-M epitope substitution (T47I) in a simian-human immunodeficiency virus (SHIV) strain 89.6P-infected Mamu-A * 01 ؉ monkey is temporally correlated with the emergence of a flanking isoleucine-to-valine substitution at position 71 (I71V) of the capsid protein. An analysis of the SIV and HIV-2 sequences from the Los Alamos HIV Sequence Database revealed a significant association between any position 2 p11C, C-M epitope mutation and the I71V mutation. The T47I mutation alone is associated with significant decreases in viral protein expression, infectivity, and replication, and these deficiencies are restored to wild-type levels with the introduction of the flanking I71V mutation. Together, these data suggest that a compensatory mutation is selected for in SHIV strain 89.6P to facilitate the escape of that virus from CTL recognition of the dominant p11C, C-M epitope.

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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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Viral Escape from Dominant Simian Immunodeficiency Virus Epitope-Specific Cytotoxic T Lymphocytes in DNA-Vaccinated Rhesus Monkeys

Cited by 153 publications

References 32 publications

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Simian-Human Immunodeficiency Virus Escape from Cytotoxic T-Lymphocyte Recognition at a Structurally Constrained Epitope

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

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Viral Escape from Dominant Simian Immunodeficiency Virus Epitope-Specific Cytotoxic T Lymphocytes in DNA-Vaccinated Rhesus Monkeys

Cited by 153 publications

References 32 publications

Understanding the Failure of CD8+T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Understanding the Failure of CD8+T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Simian-Human Immunodeficiency Virus Escape from Cytotoxic T-Lymphocyte Recognition at a Structurally Constrained Epitope

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

Contact Info

Product

Resources

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Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

Understanding the Failure of CD8⁺T-Cell Vaccination against Simian/Human Immunodeficiency Virus

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