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Human immunodeficiency virus type 1 Nef protein inhibits NF-kappa B induction in human T cells
T M Niederman1, J V Garcia, W R Hastings
1Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110.
Insights
The HIV-1 Nef protein inhibits NF-kappa B activation, a key factor in reactivating latent virus. This discovery sheds light on how Nef impacts HIV-1 transcription and T-cell signaling.
Area of Science:
- Molecular Virology
- Immunology
Background:
- Human immunodeficiency virus type 1 (HIV-1) establishes persistent, latent infections in CD4+ T lymphocytes.
- Reactivation of latent HIV-1 requires host cell activation mediated by T-cell mitogens and the transcription factor NF-kappa B.
Purpose of the Study:
- To investigate the role of the HIV-1-encoded Nef protein in regulating NF-kappa B activity and subsequent viral gene expression.
- To determine if Nef affects other transcription factors involved in HIV-1 regulation.
Main Methods:
- Assessed the effect of Nef on NF-kappa B DNA-binding activity induced by T-cell mitogens.
- Examined Nef's impact on the DNA-binding activity of transcription factors SP-1, USF, URS, and NF-AT.
- Measured Nef's inhibition of HIV-1 and interleukin 2 (IL-2)-directed gene expression.
Main Results:
- Nef protein inhibits the induction of NF-kappa B DNA-binding activity by T-cell mitogens.
- Nef does not affect the DNA-binding activity of SP-1, USF, URS, and NF-AT.
- Nef inhibits HIV-1 and IL-2 gene expression, with HIV-1 transcriptional effects dependent on an intact NF-kappa B-binding site.
- Nef appears to interfere with T-cell receptor complex signaling to inhibit NF-kappa B induction.
Conclusions:
- Defective NF-kappa B recruitment, mediated by Nef, may explain its negative transcriptional effects on HIV-1 and IL-2 promoters.
- Nef's inhibition of NF-kappa B induction suggests a mechanism for controlling viral latency and T-cell activation.
Abstract:
Human immunodeficiency virus type 1 (HIV-1) can establish a persistent and latent infection in CD4+ T lymphocytes (W. C. Greene, N. Engl. J. Med. 324:308-317, 1991; S. M. Schnittman, M. C. Psallidopoulos, H. C. Lane, L. Thompson, M. Baseler, F. Massari, C. H. Fox, N. P. Salzman, and A. S. Fauci, Science 245:305-308, 1989). Production of HIV-1 from latently infected cells requires host cell activation by T-cell mitogens (T. Folks, D. M. Powell, M. M. Lightfoote, S. Benn, M. A. Martin, and A. S. Fauci, Science 231:600-602, 1986; D. Zagury, J. Bernard, R. Leonard, R. Cheynier, M. Feldman, P. S. Sarin, and R. C. Gallo, Science 231:850-853, 1986). This activation is mediated by the host transcription factor NF-kappa B [G. Nabel and D. Baltimore, Nature (London) 326:711-717, 1987]. We report here that the HIV-1-encoded Nef protein inhibits the induction of NF-kappa B DNA-binding activity by T-cell mitogens. However, Nef does not affect the DNA-binding activity of other transcription factors implicated in HIV-1 regulation, including SP-1, USF, URS, and NF-AT. Additionally, Nef inhibits the induction of HIV-1- and interleukin 2-directed gene expression, and the effect on HIV-1 transcription depends on an intact NF-kappa B-binding site. These results indicate that defective recruitment of NF-kappa B may underlie Nef's negative transcriptional effects on the HIV-1 and interleukin 2 promoters. Further evidence suggests that Nef inhibits NF-kappa B induction by interfering with a signal derived from the T-cell receptor complex.