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Terça-feira, 21.07.15

In vivo analysis of Nef’s role in HIV-1 replication, systemic T cell activation and CD4 + T cell loss

 

In vivo analysis of Nef’s role in HIV-1 replication, systemic T cell activation and CD4 + T cell loss

Richard L Watkins, John L Foster* and J Victor Garcia*

*Corresponding authors: John L Foster john_foster@med.unc.edu - J V Garciavictor_garcia@med.unc.edu

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Retrovirology 2015, 12:61  doi:10.1186/s12977-015-0187-z

Published: 14 July 2015

Abstract

Nef is a multifunctional HIV-1 protein critical for progression to AIDS. Humans infected with nef(−) HIV-1 have greatly delayed or no disease consequences. We have contrasted nef(−) and nef(+) infection of BLT humanized mice to better characterize Nef’s pathogenic effects.

Mice were inoculated with CCR5-tropic HIV-1 JRCSF (JRCSF) or JRCSF with an irreversibly inactivated nef (JRCSFNefdd). In peripheral blood (PB), JRCSF exhibited high levels of viral RNA (peak viral loads of 4.71 × 10 6  ± 1.23 × 10 6 copies/ml) and a progressive, 75% loss of CD4 + T cells over 17 weeks. Similar losses were observed in CD4 + T cells from bone marrow, spleen, lymph node, lung and liver but thymocytes were not significantly decreased. JRCSFNefdd also had high peak viral loads (2.31 × 10 6  ± 1.67 × 10 6 ) but induced no loss of PB CD4 + T cells. In organs, JRCSFNefdd produced small, but significant, reductions in CD4 + T cell levels and did not affect the level of thymocytes. Uninfected mice have low levels of HLA-DR + CD38 +CD8 + T cells in blood (1–2%). Six weeks post inoculation, JRCSF infection resulted in significantly elevated levels of activated CD8 + T cells (6.37 ± 1.07%). T cell activation coincided with PB CD4 + T cell loss which suggests a common Nef-dependent mechanism. At 12 weeks, in JRCSF infected animals PB T cell activation sharply increased to 19.7 ± 2.9% then subsided to 5.4 ± 1.4% at 14 weeks. HLA-DR + CD38 + CD8 + T cell levels in JRCSFNefdd infected mice did not rise above 1–2% despite sustained high levels of viremia. Interestingly, we also noted that in mice engrafted with human tissue expressing a putative protective HLA-B allele (B42:01), JRCSFNefdd exhibited a substantial (200-fold) reduced viral load compared to JRCSF.

Nef expression was necessary for both systemic T cell activation and substantial CD4 + T cell loss from blood and tissues. JRCSFNefdd infection did not activate CD8 + T cells or reduce the level of CD4 + T cells in blood but did result in a small Nef-independent decrease in CD4 + T cells in organs. These observations strongly support the conclusion that viral pathogenicity is mostly driven by Nef. We also observed for the first time substantial host-specific suppression of HIV-1 replication in a small animal infection model.

Keywords:

HIV-1; Nef; Replication; Pathogenesis

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por cyto às 17:53



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