HIV-1 infection of human macrophages directly induces viperin which inhibits viral production

Nasr, Najla; Maddocks, Susan; Turville, Stuart; Harman, Andrew N.; Woolger, Natalie; Helbig, Karla J.; Wilkinson, John; Bye, Chris R.; Wright, Thomas K.; Rambukwelle, Dharshini; Donaghy, Heather; Beard, Michael R.; Cunningham, Anthony L.

doi:10.1182/blood-2012-01-407395

Cited by 201 publications

(225 citation statements)

References 50 publications

Supporting

Mentioning

209

Contrasting

Order By: Relevance

“…This result is in agreement with previous reports showing that HIV-1 infection of macrophages neither triggered IRF3 pathways nor induced type-I IFN gene expression (78)(79)(80)(81). Moreover, a recent report showed that mDCs and macrophages fail to induce expression of all known type-I and type-III IFN genes in response to HIV-1 (82).…”

Section: Hiv-1-mediated Baff Induction Is Modulated By the Macrophagesupporting

confidence: 83%

HIV-1–Mediated BAFF Secretion in Macrophages Does Not Require Endosomal TLRs, Type-I IFN, and Nef, but Depends on the Cellular Phenotype Status

Gómez

Ouellet

Deshière

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

HIV-1 infection is characterized by persistent viral replication, chronic immune activation, and CD4+ T cell depletion. Moreover, several immune dysfunctions are observed in cells that are not targeted by the virus, such as B cells. Some B cell abnormalities include hypergammaglobulinemia, nonspecific B cell activation, class switching, increased cell turnover, breakage of tolerance, and a loss of the capacity to generate and maintain memory. Several cytokines and growth factors that are increased in the serum of HIV-1–infected individuals have been suggested to directly or indirectly trigger B cell activation, and one of these is BAFF. In this study, we investigate the ability of fully competent (R5-tropic) HIV-1 to induce BAFF production by monocyte-derived macrophages (MDMs). We demonstrate here that HIV-1 drives BAFF production in MDMs in a type-I IFN– and TLR-independent manner. Moreover, we determine that HIV-1 Nef accessory protein is dispensable in BAFF upregulation as a nef-deleted HIV-1 strain is still able to increase BAFF at levels similar to the wild type strain. Finally, we show that the macrophage phenotype status affects HIV-1 replication and BAFF induction, as both were abrogated in MDMs displaying a M1 phenotype. This study provides new useful information about the increased levels of BAFF observed during HIV-1 infection and highlights the importance of macrophages as a source of BAFF, a phenomenon that might contribute to B cell dysfunctions at inflammatory tissue sites in infected individuals.

show abstract

Section: Hiv-1-mediated Baff Induction Is Modulated By the Macrophagesupporting

confidence: 83%

HIV-1–Mediated BAFF Secretion in Macrophages Does Not Require Endosomal TLRs, Type-I IFN, and Nef, but Depends on the Cellular Phenotype Status

Gómez

Ouellet

Deshière

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…The consensus from these studies is that viperin likely exerts its activity through different pathways that depend on the particular virus and that it interacts with multiple cellular and viral proteins in the process (19,27,31,33,34). Previous studies, using a truncated version of viperin, recombinantly produced and purified from E. coli, have demonstrated that the enzyme cleaves SAM to form 5Ј-dA (22), which is the hallmark reaction of radical SAM enzymes.…”

Section: Discussionmentioning

confidence: 99%

Does Viperin Function as a Radical S-Adenosyl-l-methionine-dependent Enzyme in Regulating Farnesylpyrophosphate Synthase Expression and Activity?

Makins

Ghosh²,

Román‐Meléndez³

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Charles SamuelViperin is an endoplasmic reticulum-associated antiviral responsive protein that is highly up-regulated in eukaryotic cells upon viral infection through both interferon-dependent and independent pathways. Viperin is predicted to be a radical S-adenosyl-L-methionine (SAM) enzyme, but it is unknown whether viperin actually exploits radical SAM chemistry to exert its antiviral activity. We have investigated the interaction of viperin with its most firmly established cellular target, farnesyl pyrophosphate synthase (FPPS). Numerous enveloped viruses utilize cholesterol-rich lipid rafts to bud from the host cell membrane, and it is thought that by inhibiting FPPS activity (and therefore cholesterol synthesis), viperin retards viral budding from infected cells. We demonstrate that, consistent with this hypothesis, overexpression of viperin in human embryonic kidney cells reduces the intracellular rate of accumulation of FPPS but does not inhibit or inactivate FPPS. The endoplasmic reticulum-localizing, N-terminal amphipathic helix of viperin is specifically required for viperin to reduce cellular FPPS levels. However, although viperin reductively cleaves SAM to form 5-deoxyadenosine in a slow, uncoupled reaction characteristic of radical SAM enzymes, this cleavage reaction is independent of FPPS. Furthermore, mutation of key cysteinyl residues ligating the catalytic [Fe 4 S 4 ] cluster in the radical SAM domain, surprisingly, does not abolish the inhibitory activity of viperin against FPPS; indeed, some mutations potentiate viperin activity. These observations imply that viperin does not act as a radical SAM enzyme in regulating FPPS. Radical S-adenosyl-L-methionine-dependent (SAM)3 enzymes constitute a superfamily of enzymes that use SAM to generate free radicals (1-4). The superfamily is typified by a common CXXXCXXC motif, the cysteinyl residues of which coordinate a [Fe 4 S 4 ] cluster that is essential for radical generation. These enzymes catalyze a remarkably wide range of reactions involving an equally diverse set of substrates (2). For example, radical SAM-dependent enzymes participate in the biosynthesis of herbicides, antibiotics, vitamins, co-factors such as biotin and thiamin, and various other natural products (2, 5-8). They also function in the modification of ribosomal and transfer RNAs (9, 10) and DNA repair (11) and in the post-translational modification of peptides and proteins (12)(13)(14). Sequence analyses indicate that there are potentially thousands of members of the radical SAM superfamily, but to date, relatively few of these enzymes have been isolated and characterized (15, 16). Radical SAM enzymes were until recently thought to be confined to the microbial realm but intriguingly have now been identified in higher aerobic organisms, including plants and animals (3).Central to the mechanism of all radical SAM enzymes is the generation of a highly reactive 5Ј-deoxyadenosyl radical (Ado ⅐ ) (1,4,17). This is accomplished through one-electron reduction of SAM by the [Fe 4...

show abstract

“…This pathway is induced by host PRRs, among which nucleic acid sensors are known to play particularly important roles [2]. In contrast to the typical scenario, HIV-1 infection of T-cells and macrophages does not stimulate IRF3 activation and fails to induce IFN expression, but does lead to expression of a subset of ISGs [3][4][5]. However, it has been reported that HIV-1 genomic RNA can induce IFN responses in specific cell culture systems via toll-like receptor 7 and retinoid-acid inducible gene I [6][7][8].…”

Section: Human Immunodeficiency Virus Type 1 (Hiv-1) Is the Cause Ofmentioning

confidence: 99%

Caught in translation: innate restriction of HIV mRNA translation by a schlafen family protein

2012

View full text Add to dashboard Cite

HIV-1 infection of human macrophages directly induces viperin which inhibits viral production

Cited by 201 publications

References 50 publications

HIV-1–Mediated BAFF Secretion in Macrophages Does Not Require Endosomal TLRs, Type-I IFN, and Nef, but Depends on the Cellular Phenotype Status

HIV-1–Mediated BAFF Secretion in Macrophages Does Not Require Endosomal TLRs, Type-I IFN, and Nef, but Depends on the Cellular Phenotype Status

Does Viperin Function as a Radical S-Adenosyl-l-methionine-dependent Enzyme in Regulating Farnesylpyrophosphate Synthase Expression and Activity?

Caught in translation: innate restriction of HIV mRNA translation by a schlafen family protein

Contact Info

Product

Resources

About