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Antiretroviral compounds affect the granule-dependent mechanisms of lysis in CD8 T cells

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Background

Cytotoxic T-lymphocytes (CTLs) are essential for suppression of viral replication and, in particular, they have a pivotal role in control of progression of HIV infection. It has been demonstrated that HIV-specific CTL responses are defective in HIV-infected patients undergoing highly active antiretroviral therapy (HAART). In this study we investigated the effects of antiretroviral compounds on the granule-dependent mechanisms of lysis in peripheral blood mononuclear cells (PBMCs).

Materials and methods

PBMCs of 10 HCs were incubated with 3 different antiretroviral drugs combinations: combination A: AZT (NRTI) + 3TC (NRTI) + IDV (PI); combination B: d4T (NRTI) + ddI (NRTI) + NFV (PI); combination C: 3TC (NRTI) + EFV (NNRTI) + TDF (NRTI). To evaluate the CTLs function we measured: production and release of granule-dependent effector molecules (perforin, granzyme B); production and release of granule-independent effector molecules (IFN-gamma, TNF-alpha); degranulation markers (LAMP1 and LAMP2). To assest the immunomodulant effects of IL-15, PBMCs were also incubate in presence of this cytokyne.

Results

Antiretroviral compounds reduce the granzyme B and perforin production (while they don't affect the IFN-gamma and TNF-alpha production). Moreover, one of the 3 tested combinations of antiretroviral compounds (combination B) reduces the granzyme B release and affects the degranulation in CTLs. IL-15 increases the levels of granzyme B and perforin.

Conclusion

Antiretroviral compounds mainly affect the expression of genes encoding for Pfp and GranzB, and deteriorate the mechanism of degranulation in CD8+ T cells. L-15 restores both the granule-dependent and the granule-independent cytotoxic mechanisms. Basd on these data, IL-15 seems to be useful in overcoming the negative effects of antiretroviral compounds on the cytotoxic function.

Author information

Correspondence to Anita Parmigiani.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Keywords

  • Mononuclear Cell
  • Peripheral Blood Mononuclear Cell
  • Viral Replication
  • Drug Combination
  • Immunomodulant Effect