Association of Nef with p21-activated kinase 2 is dispensable for efficient human immunodeficiency virus type 1 replication and cytopathicity in Ex vivo-infected human lymphoid tissue

被引:32
|
作者
Schindler, Michael
Rajan, Devi
Specht, Anke
Ritter, Carolin
Pulkkinen, Kati
Saksela, Kalle
Kirchhoff, Frank [1 ]
机构
[1] Univ Ulm Klinikum, Inst Virol, D-89081 Ulm, Germany
[2] Univ Tampere, Inst Med Technol, Tampere 33014, Finland
[3] Tampere Univ Hosp, Tampere 33014, Finland
[4] Univ Helsinki, Dept Virol, Haartman Inst, Helsinki 00014, Finland
[5] Helsinki Univ Hosp, Helsinki 00014, Finland
[6] Heinrich Pette Inst, D-20251 Hamburg, Germany
关键词
D O I
10.1128/JVI.01436-07
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Interaction of the human immunodeficiency virus type 1 (HIV-1) Nef protein with p21-activated kinase 2 (PAK2) has been proposed to play a role in T-cell activation, viral replication, apoptosis, and progression to AIDS. However, these hypotheses were based on results obtained using Nef mutants impaired in multiple functions. Recently, it was reported that Nef residue F191 is specifically involved in PAK2 binding. However, only a limited number of Nef activities were investigated in these studies. To further evaluate the role of F191 in Nef function and to elucidate the biological relevance of Nef-PAK2 interaction, we performed a comprehensive analysis of HIV-1 Nef mutants carrying F191H and F191R mutations. We found that the F191H mutation reduces and the F191R mutation disrupts the association of Nef with PAK2. Both mutants upregulated the major histocompatibility complex 11 (MHC-II) -associated invariant chain and downregullated CD4, MHC-I, and CD28, although with reduced efficiency for the latter. Furthermore, the F19IH/R changes neither affected the levels of interleukin-2 receptor expression and apoptosis of HIV-1-infected primary T cells nor reduced Nef-mediated induction of NFAT. Unexpectedly, the F191H change markedly reduced and the F191R mutation disrupted the ability of Nef to enhance virion infectivity in P4-CCR5 indicator cells but not in TZM-bl cells or peripheral blood mononuclear cells. Most importantly, all HIV-1 Nef mutants replicated efficiently and caused CD4(+) T-cell depletion in ex vivo-infected human lymphoid tissue. Altogether, our data show that the interaction of Nef with PAK2 does not play a major role in T-cell activation, viral replication, and apoptosis.
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收藏
页码:13005 / 13014
页数:10
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