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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-1 JRCSF  (JRCSF) or JRCSF with an irreversibly inactivated  nef  (JRCSFNef dd ). 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. JRCSFNef dd  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, JRCSFNef dd  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 JRCSFNef dd  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), JRCSFNef dd  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. JRCSFNef dd  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.    Electronic supplementary material  The online version of this article (doi:10.1186/s12977-015-0187-z) contains supplementary material, which is available to authorized users.

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