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

Oliver T. Fackler, Dietlinde Wolf, H. Oliver Weber, Bernd Laffert, Paola D'Aloja, Beatrice Schuler-Thurner, Rebeca Geffin, Kalle Saksela, Matthias Geyer, B. Matija Peterlin, Gerold Schuler, Andreas S. Baur

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)1294-1299
Number of pages6
JournalCurrent Biology
Volume11
Issue number16
DOIs
StatePublished - Aug 21 2001
Externally publishedYes

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T-cells
Human immunodeficiency virus 1
Proline
proline
HIV-1
T-lymphocytes
T-Lymphocytes
T-Cell Antigen Receptor
Viruses
Dendritic Cells
Human Immunodeficiency Virus nef Gene Products
Protein Isoforms
dendritic cells
virus replication
Coculture Techniques
Viral Load
Structural analysis
Disease Progression
viruses
receptors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)

Cite this

Fackler, O. T., Wolf, D., Weber, H. O., Laffert, B., D'Aloja, P., Schuler-Thurner, B., ... Baur, A. S. (2001). A natural variability in the proline-rich motif of Nef modulates HIV-1 replication in primary T cells. Current Biology, 11(16), 1294-1299. https://doi.org/10.1016/S0960-9822(01)00373-6

A natural variability in the proline-rich motif of Nef modulates HIV-1 replication in primary T cells. / Fackler, Oliver T.; Wolf, Dietlinde; Weber, H. Oliver; Laffert, Bernd; D'Aloja, Paola; Schuler-Thurner, Beatrice; Geffin, Rebeca; Saksela, Kalle; Geyer, Matthias; Peterlin, B. Matija; Schuler, Gerold; Baur, Andreas S.

In: Current Biology, Vol. 11, No. 16, 21.08.2001, p. 1294-1299.

Research output: Contribution to journalArticle

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 2001, 'A natural variability in the proline-rich motif of Nef modulates HIV-1 replication in primary T cells', Current Biology, vol. 11, no. 16, pp. 1294-1299. https://doi.org/10.1016/S0960-9822(01)00373-6
Fackler OT, Wolf D, Weber HO, Laffert B, D'Aloja P, Schuler-Thurner B et al. A natural variability in the proline-rich motif of Nef modulates HIV-1 replication in primary T cells. Current Biology. 2001 Aug 21;11(16):1294-1299. https://doi.org/10.1016/S0960-9822(01)00373-6
Fackler, Oliver T. ; Wolf, Dietlinde ; Weber, H. Oliver ; Laffert, Bernd ; D'Aloja, Paola ; Schuler-Thurner, Beatrice ; Geffin, Rebeca ; Saksela, Kalle ; Geyer, Matthias ; Peterlin, B. Matija ; Schuler, Gerold ; Baur, Andreas S. / A natural variability in the proline-rich motif of Nef modulates HIV-1 replication in primary T cells. In: Current Biology. 2001 ; Vol. 11, No. 16. pp. 1294-1299.
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