Fitness Costs and Diversity of the Cytotoxic T Lymphocyte (CTL) Response Determine the Rate of CTL Escape during Acute and Chronic Phases of HIV Infection

Author:

Ganusov Vitaly V.12,Goonetilleke Nilu3,Liu Michael K. P.3,Ferrari Guido4,Shaw George M.5,McMichael Andrew J.3,Borrow Persephone6,Korber Bette T.17,Perelson Alan S.1

Affiliation:

1. Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico 87545

2. Department of Microbiology, University of Tennessee, Knoxville, Tennessee 37996

3. Weatherall Institute of Molecular Medicine, Oxford University, Oxford, United Kingdom

4. Duke University Medical Research, Duke University, Durham, North Carolina 27710

5. Department of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama

6. The Jenner Institute, University of Oxford, Compton, United Kingdom

7. Santa Fe Institute, Santa Fe, New Mexico 87501

Abstract

ABSTRACT HIV-1 often evades cytotoxic T cell (CTL) responses by generating variants that are not recognized by CTLs. We used single-genome amplification and sequencing of complete HIV genomes to identify longitudinal changes in the transmitted/founder virus from the establishment of infection to the viral set point at 1 year after the infection. We found that the rate of viral escape from CTL responses in a given patient decreases dramatically from acute infection to the viral set point. Using a novel mathematical model that tracks the dynamics of viral escape at multiple epitopes, we show that a number of factors could potentially contribute to a slower escape in the chronic phase of infection, such as a decreased magnitude of epitope-specific CTL responses, an increased fitness cost of escape mutations, or an increased diversity of the CTL response. In the model, an increase in the number of epitope-specific CTL responses can reduce the rate of viral escape from a given epitope-specific CTL response, particularly if CD8 + T cells compete for killing of infected cells or control virus replication nonlytically. Our mathematical framework of viral escape from multiple CTL responses can be used to predict the breadth and magnitude of HIV-specific CTL responses that need to be induced by vaccination to reduce (or even prevent) viral escape following HIV infection.

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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