Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone.

Folks, Thomas M.; Clouse, Kathleen A.; Justement, J. Shawn; Rabson, Arnold B.; Duh, Elia J.; Kehrl, John H.; Fauci, Anthony S.

doi:10.1073/pnas.86.7.2365

Cited by 650 publications

(458 citation statements)

References 35 publications

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“…less than 1 in 10 6 of resting CD4+ T cells (Finzi et al, 1997). Moreover, there are a few available latently HIV-1-infected cell lines such as ACH2 (Folks et al, 1989), J1.1 (Perez et al, 1991), and U1 (Folks et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Establishment of novel cell lines latently infected with human immunodeficiency virus 1

Oh¹,

Kim²,

Hong³

et al. 2011

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Section: Introductionmentioning

confidence: 99%

Establishment of novel cell lines latently infected with human immunodeficiency virus 1

Oh¹,

Kim²,

Hong³

et al. 2011

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“…Although a 40 to 50% increase in TNF levels (observed upon expression of Nef in latently infected T cells) would have a minor effect on a single-replication-cycle basis, even smaller changes in the replication potential of HIV could exert a dramatic effect on the propagation of the virus in infected individuals. It should also be noted that the latent virus present in ACH2 cells encodes a functional nef gene (12), which must also contribute to the observed increase in TNF expression and partially mask the effects due to overexpression of Nef-GFP. Increased surface expression of TNF might enhance HIV transcription in a paratropic or autotropic fashion.…”

Section: Discussionmentioning

confidence: 99%

“…However, it remains unclear whether elevated TNF levels are the consequence of a specific viral product (e.g., Nef) or rather represent a general state of immune activation against HIV. TNF is also a potent activator of HIV transcription (12), and it would be expected that high levels of TNF in serum accelerate virus spread and disease progression. We have shown that Nef-GFP introduced into a chronically infected T-cell line which responds to TNF and PMA resulted in increased HIV expression.…”

Section: Discussionmentioning

confidence: 99%

“…The physiological consequences of TNF modulation during HIV infection are complex. TNF is a potent activator of HIV transcription (12), and it would be expected that high levels of TNF could accelerate virus spread and disease progression. We decided to investigate whether Nef-mediated changes in TNF expression could affect the rate of HIV production.…”

Section: Cell Surface Expression Of Tnf and Light Is Increased In T Cmentioning

confidence: 99%

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Human Immunodeficiency Virus Type 1 Nef Mediates Sustained Membrane Expression of Tumor Necrosis Factor and the Related Cytokine LIGHT on Activated T Cells

Lama

Ware

2000

J Virol

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Human immunodeficiency virus (HIV) Nef downregulates the antigen recognition molecules major histocompatibility complex class I and CD4. Downregulation of surface CD4 by Nef relies on the ability of this viral protein to redirect the endocytic machinery to CD4. However, by redirecting the endocytic machinery, Nef may affect the internalization rates of other proteins. Here we show that Nef simultaneously enhances surface expression of the effector cytokines tumor necrosis factor (TNF) and LIGHT, leading to enhanced cytokine activity. A dileucine motif in Nef, which is essential for CD4 downregulation and is involved in the recruitment of adapter protein complexes by Nef, was required to increase surface levels of both cytokines. The physiological impact of the Nef-mediated interference with endocytosis was demonstrated by the fact that a TNFresponsive T-cell line chronically infected with HIV produced higher levels of p24 viral protein following expression of a Nef-green fluorescent protein (GFP) fusion protein. This enhancement was dependent on the levels of membrane-bound TNF, since it was abrogated by a recombinant soluble TNF receptor. Expression of Nef-GFP in human 293T cells reduced the endocytosis of LIGHT, whereas at the same time CD4 internalization was accelerated. Taken together, these results suggest that in infected cells Nef interferes with the internalization of these effector cytokines. By increasing TNF expression, Nef could accelerate disease progression in infected individuals. These findings may help explain the pleiotropic functions that Nef plays during infection and disease.

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“…A high concentration of TNF-a may be expected to contribute to the cachexia commonly seen in the Ethiopian paiients. Also, TNF-a is an aclivalor of HIV replication [35,36], and an early production of this cytokine might accelerate the progression of the HIV infection. On the other hand, IFN-a is known lo downregulate the release of HIV [37], and a failure to produce sufficient amounts of IFN-a may result in an inability lo contain the infection.…”

Section: ]mentioning

confidence: 99%

Raised levels of tumour necrosis factor-alpha and neopterin, but not interferon-alpha, in serum of HIV-1-infected patients from Ethiopia

Ayehunie

Sönnerborg²,

Yemane-Berhan

et al. 1993

Clinical and Experimental Immunology

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SUMMARY Serum levels of tumour necrosis factor‐alpha (TNF‐α). neopterin and interferon‐alpha (IFN‐α) were determined by immunoradiometric assays in 60 HIV‐1+and 20 HIV‐1− subjects from Ethiopia. Swedish samples were used as reference material. The Ethiopian HIV‐1‘ subjects were found to have significantly increased TNF‐α and neopterin, but not IFN‐α levels. Increased levels of TNF‐α and neopterin were frequently found in Ethiopian asymptomatic subjects (37% and 41%). and the concentration increased in patients with AIDS (83% and 90% respectively). The levels of the two substances and the proportion of patients with higher TNF‐α values were lower in the corresponding Swedish subjects. The proportion of sera with raised levels of I FN‐α was very low (asymptomatic 4%, and AIDS 7%) in Ethiopian subjects. These results suggest a very early increase in the TNF‐α production and activation of the cellular immune response, and a low level of IFN‐α synthesis in the natural course of HIV infection in Ethiopia. The aberrations may contribute to a rapid progress of immunodeficiency and cachexia often seen in Ethiopian patients.

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Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone.

Cited by 650 publications

References 35 publications

Establishment of novel cell lines latently infected with human immunodeficiency virus 1

Establishment of novel cell lines latently infected with human immunodeficiency virus 1

Human Immunodeficiency Virus Type 1 Nef Mediates Sustained Membrane Expression of Tumor Necrosis Factor and the Related Cytokine LIGHT on Activated T Cells

Raised levels of tumour necrosis factor-alpha and neopterin, but not interferon-alpha, in serum of HIV-1-infected patients from Ethiopia

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