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Two types of cytotoxic lymphocyte regulation explain kinetics of immune response to human immunodeficiency virus.

ABSTRACT: The organization of the cytotoxic T lymphocyte (CTL) response at organismal level is poorly understood. We propose a mathematical model describing the interaction between HIV and its host that explains 20 quantitative observations made in HIV-infected individuals and simian immunodeficiency virus-infected monkeys, including acute infection and response to various antiretroviral therapy regimens. The model is built on two modes of CTL activation: direct activation by infected cells and indirect activation by CD4 helper cells activated by small amounts of virus. Effective infection of helper cells by virus leads to a stable chronic infection at high virus load. We assume that CTLs control virus by killing infected cells. We explain the lack of correlation between the CTL number and the virus decay rate in therapy and predict that individuals with a high virus load can be switched to a low-viremia state that will maintain stability after therapy, but the switch requires fine adjustment of therapy regimen based on the model and individual parameters.

SUBMITTER: Rouzine IM

PROVIDER: S-EPMC1334670 | biostudies-literature | 2006 Jan

REPOSITORIES: biostudies-literature

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Two types of cytotoxic lymphocyte regulation explain kinetics of immune response to human immunodeficiency virus.

Rouzine I M IM Sergeev R A RA Glushtsov A I AI

Proceedings of the National Academy of Sciences of the United States of America 20060105 3

The organization of the cytotoxic T lymphocyte (CTL) response at organismal level is poorly understood. We propose a mathematical model describing the interaction between HIV and its host that explains 20 quantitative observations made in HIV-infected individuals and simian immunodeficiency virus-infected monkeys, including acute infection and response to various antiretroviral therapy regimens. The model is built on two modes of CTL activation: direct activation by infected cells and indirect a ...[more]

PMID: 16407101

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Project description:CD8(+) cytotoxic T lymphocytes (CTL) are strong mediators of human immunodeficiency virus type 1 (HIV-1) control, yet HIV-1 frequently mutates to escape CTL recognition. In an analysis of sequences in the Los Alamos HIV-1 database, we show that emerging CTL escape mutations were more often present at lower frequencies than the amino acid(s) that they replaced. Furthermore, epitopes that underwent escape contained amino acid sites of high variability, whereas epitopes persisting at high frequencies lacked highly variable sites. We therefore infer that escape mutations are likely to be associated with weak functional constraints on the viral protein. This was supported by an extensive analysis of one subject for whom all escape mutations within defined CTL epitopes were studied and by an analysis of all reported escape mutations of defined CTL epitopes in the HIV Immunology Database. In one of these defined epitopes, escape mutations involving the substitution of amino acids with lower database frequencies occurred, and the epitope soon reverted back to the sensitive form. We further show that this escape mutation substantially diminished viral fitness in in vitro competition assays. Coincident with the reversion in vivo, we observed the fixation of a mutation 3 amino acids C terminal to the epitope, coincident with the ablation of the corresponding CTL response. The C-terminal mutation did not restore replication fitness reduced by the escape mutation in the epitope and by itself had little effect on replication fitness. Therefore, this C-terminal mutation presumably impaired the processing and presentation of the epitope. Finally, for one persistent epitope, CTL cross-reactivity to a mutant form may have suppressed the mutant to undetected levels, whereas for two other persistent epitopes, each of two mutants showed poor cross-reactivity and appeared in the subject at later time points. Thus, a viral dynamic exists between the advantage of immune escape, peptide cross-reactivity, and the disadvantage of lost replication fitness, with the balance playing an important role in determining whether a CTL epitope will persist or decline during infection.

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Two types of cytotoxic lymphocyte regulation explain kinetics of immune response to human immunodeficiency virus.

Publications

Two types of cytotoxic lymphocyte regulation explain kinetics of immune response to human immunodeficiency virus.

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