Defining CTL-induced pathology: implications for HIV.
The relationship between virus and host cells is multifactorial and nonlinear. This indicates that the effect of an immune response on infection can lead to several different outcomes. These include severe immunopathology. We seek to define properties of CTL-induced pathology in viral infections and examine the implications for HIV disease progression. We find that CTL-induced pathology is observed if the rate of viral replication is fast relative to the CTL responsiveness of the host. Theoretical predictions are consistent with empirical data on LCMV infection. These conditions are also sufficient to induce pathology in HIV infection. However, the absence of HIV-specific CTL can result in an equivalent depletion of the CD4 T cell pool as a consequence of the short life span of activated T cells. A mathematical model describing the evolution of HIV coreceptor usage in the context of lytic and nonlytic CD8 cell responses might account for the relatively long time span required to result in disease. Viral evolution toward parameter ranges allowing CTL-induced pathology is difficult to achieve. It requires the emergence of fast viral replication together with escape from nonlytic CTL responses. However, according to the model, fast viral replication can result in the evolution of virus strains that are susceptible to chemokine-mediated inhibition of viral replication.
Wodarz
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Institute for Advanced Study, Olden Lane, Princeton, New Jersey 08540, USA. wodarz@ias.edu
Krakauer
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D005075:Biological Evolution; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D006678:HIV / Q000254:growth & development / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008212:Lymphocyte Depletion; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000473:pathology; D008954:Models, Biological; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*
D019713:Receptors, CCR5; D019718:Receptors, CXCR4