A natural variability in the proline-rich motif of Nef modulates HIV-1 replication in primary T cells

被引:43
作者
Fackler, OT
Wolf, D
Weber, HO
Laffert, B
D'Aloja, P
Schuler-Thurner, B
Geffin, R
Saksela, K
Geyer, M
Peterlin, BM
Schuler, G
Baur, AS [1 ]
机构
[1] Univ Miami, Dept Pediat, Miami, FL 33136 USA
[2] Univ Erlangen Nurnberg, Dept Dermatol, D-91052 Erlangen, Germany
[3] Univ Heidelberg, Inst Hyg, Dept Virol, D-69120 Heidelberg, Germany
[4] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Med, San Francisco, CA 94143 USA
[5] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Microbiol, San Francisco, CA 94143 USA
[6] Univ Calif San Francisco, Howard Hughes Med Inst, Dept Immunol, San Francisco, CA 94143 USA
[7] Tampere Univ, Inst Med Technol, FIN-33101 Tampere, Finland
关键词
D O I
10.1016/S0960-9822(01)00373-6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In the infected host, the Nef protein of HIV/SIV is required for high viral loads and thus disease progression [1-3]. Recent evidence indicates that Nef enhances replication in the T cell compartment after the virus is transmitted from dendritic cells (DC) [4]. The underlying mechanism, however, is not clear. Here, we report that a natural variability in the proline-rich motif (R71T) profoundly modulated Nef-stimulated viral replication in primary T cells of immature dendritic cell/T cell cocultures. Whereas both Nef variants (R/T-Nef) downregulated CD4, only the isoform supporting viral replication (R-Nef) efficiently interacted with signaling molecules of the T cell receptor (TCR) environment and stimulated cellular activation. Structural analysis suggested that the R to T conversion induces conformational changes, altering the flexibility of the loop containing the PxxP motif and hence its ability to bind cellular partners. Our report suggests that functionally and conformationally distinct Nef isoforms modulate HIV replication on the interaction level with the TCR-signaling environment once the virus enters the T cell compartment.
引用
收藏
页码:1294 / 1299
页数:6
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