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The role of the cytotoxic T-lymphocyte response and virus cytopathogenicity in the virus decline during antiviral therapy.

ABSTRACT: Although it is clear that HIV can lyse HIV-infected CD4 T cells, it is still controversial whether the depletion of CD4 T cells seen in HIV-infected patients after years of asymptomatic disease is caused by the direct cytopathic effects of the virus or is mediated by the immune response. Assuming the initial decline in viraemia during highly active antiretroviral therapy (HAART) is caused by the death of cells productively infected with HIV, I investigate how the rate of the virus decline is affected by the efficiency of the cytotoxic T-lymphocyte (CTL) response. I find that whether the stronger immune response causes a more rapid virus decline depends critically on how the virus is controlled by the CTL response (lytic versus non-lytic mechanisms). Moreover, variation in the efficiency of the immune response does not always cause variation in the rate of the virus decline (and, therefore, in the death rate of infected cells), implying that the constancy of the virus decline rate measured in different patients does not necessarily indicate that the virus is cytopathic. The potential problems associated with the model and the approach undertaken are also discussed.

SUBMITTER: Ganusov VV

PROVIDER: S-EPMC1691396 | biostudies-literature | 2003 Jul

REPOSITORIES: biostudies-literature

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The role of the cytotoxic T-lymphocyte response and virus cytopathogenicity in the virus decline during antiviral therapy.

Ganusov Vitaly V VV

Proceedings. Biological sciences 20030701 1523

Although it is clear that HIV can lyse HIV-infected CD4 T cells, it is still controversial whether the depletion of CD4 T cells seen in HIV-infected patients after years of asymptomatic disease is caused by the direct cytopathic effects of the virus or is mediated by the immune response. Assuming the initial decline in viraemia during highly active antiretroviral therapy (HAART) is caused by the death of cells productively infected with HIV, I investigate how the rate of the virus decline is aff ...[more]

PMID: 12965018

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Project description:UnlabelledCuring HIV-1 infection will require elimination of persistent cellular reservoirs that harbor latent virus in the face of combination antiretroviral therapy (cART). Proposed immunotherapeutic strategies to cure HIV-1 infection include enhancing lysis of these infected cells by cytotoxic T lymphocytes (CTL). A major challenge in this strategy is overcoming viral immune escape variants that have evaded host immune control. Here we report that naive CD8(+) T cells from chronic HIV-1-infected participants on long-term cART can be primed by dendritic cells (DC). These DC must be mature, produce high levels of interleukin 12p70 (IL-12p70), be responsive to CD40 ligand (CD40L), and be loaded with inactivated, autologous HIV-1. These DC-primed CD8(+) T cell responders produced high levels of gamma interferon (IFN-γ) in response to a broad range of both conserved and variable regions of Gag and effectively killed CD4(+) T cell targets that were either infected with the autologous latent reservoir-associated virus or loaded with autologous Gag peptides. In contrast, HIV-1-specific memory CD8(+) T cells stimulated with autologous HIV-1-loaded DC produced IFN-γ in response to a narrow range of conserved and variable Gag peptides compared to the primed T cells and most notably, displayed significantly lower cytolytic function. Our findings highlight the need to selectively induce new HIV-1-specific CTL from naive precursors while avoiding activation of existing, dysfunctional memory T cells in potential curative immunotherapeutic strategies for HIV-1 infection.ImportanceCurrent immunotherapeutic approaches aim to enhance antiviral immunity against the HIV-1 reservoir; however, it has yet to be shown whether T cells from persons on cART can recognize and eliminate virus-infected cells. We show that in persons on cART a personalized medicine approach using their dendritic cells to stimulate their naive T cells induces potent effector CTL in vitro that recognize and eradicate HIV-1-infected CD4(+) T cells. Additionally, we show that the same stimulation of existing memory T cells results in cytokine secretion but limited effector function. Our study demonstrates that the naive T cell repertoire can recognize persistent HIV-1 during cART and supports immunotherapy strategies for an HIV-1 cure that targets naive T cells, rather than existing, dysfunctional, memory T cells.

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The role of the cytotoxic T-lymphocyte response and virus cytopathogenicity in the virus decline during antiviral therapy.

Publications

The role of the cytotoxic T-lymphocyte response and virus cytopathogenicity in the virus decline during antiviral therapy.

Similar Datasets

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