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

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  • Garcia, J. Victor
    • Affiliation: School of Medicine, Division of Infectious Diseases
  • Foster, John L
    • Affiliation: School of Medicine, Division of Infectious Diseases
  • Watkins, Richard L
    • Affiliation: School of Medicine, Division of Infectious Diseases
  • Background 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. Results Mice were inoculated with CCR5-tropic HIV-1JRCSF (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 × 106 ± 1.23 × 106 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 × 106 ± 1.67 × 106) 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. Conclusions 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.
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  • Watkins et al.
  • English
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  • Retrovirology. 2015 Jul 14;12(1):61
  • BioMed Central

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