Inhibition of human immunodeficiency virus (HIV) replication by HIV-trans-activated alpha 2-interferon.

Bednarik, Daniel P.; Mosca, Joseph D.; Raj, Nitin; Pitha, Paula M.

doi:10.1073/pnas.86.13.4958

Cited by 85 publications

(41 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Type I interferons also have well-characterized antiviral effects on HIV replication in vitro (5,20,57,60). However, in vivo they are increasingly thought to play a central role in the aberrant immune system activation that may drive HIV disease progression.…”

Section: Discussionmentioning

confidence: 99%

Human Immunodeficiency Virus Viremia Induces Plasmacytoid Dendritic Cell Activation In Vivo and Diminished Alpha Interferon Production In Vitro

Tilton

Manion

Luskin

et al. 2008

J Virol

View full text Add to dashboard Cite

Human immunodeficiency virus type 1 (HIV-1) infection has been associated with perturbations of plasmacytoid dendritic cells (PDC), including diminished frequencies in the peripheral blood and reduced production of type I interferons (IFNs) in response to in vitro stimulation. However, recent data suggest a paradoxical increase in production of type 1 interferons in vivo in HIV-infected patients compared to uninfected controls. Using a flow cytometric assay to detect IFN-α-producing cells within unseparated peripheral blood mononuclear cells, we observed that short-term interruptions of antiretroviral therapy are sufficient to result in significantly reduced IFN-α production by PDC in vitro in response to CpG A ligands or inactivated HIV particles. The primary cause of diminished IFN-α production was reduced responsiveness of PDC to de novo stimulation, not diminished per cell IFN-α production or migration of cells to lymphoid organs. Real-time PCR analysis of purified PDC from patients prior to and during treatment interruptions revealed that active HIV-1 replication is associated with upregulation of type I IFN-stimulated gene expression. Treatment of hepatitis C virus-infected patients with IFN-α2b and ribavirin for hepatitis C virus infection resulted in a profound suppression of de novo IFN-α production in response to CpG A or inactivated HIV particles, similar to the response observed in HIV-infected patients. Together, these results suggest that diminished production of type I interferons in vitro by PDC from HIV-1-infected patients may not represent diminished interferon production in vivo. Rather, diminished function in vitro is likely a consequence of prior activation via type I interferons or HIV virions in vivo.

show abstract

Section: Discussionmentioning

confidence: 99%

Human Immunodeficiency Virus Viremia Induces Plasmacytoid Dendritic Cell Activation In Vivo and Diminished Alpha Interferon Production In Vitro

Tilton

Manion

Luskin

et al. 2008

J Virol

View full text Add to dashboard Cite

show abstract

“…These results suggest that IFN are less active in cell cultures than initially thought. They help explain the incomplete protection by naturally secreted IFN during HIV infection and the unsatisfactory outcome of IFN treatment in HIV-infected patients.The inhibition of human immunodeficiency virus type 1 (HIV) replication by type I interferons (IFN) was demonstrated soon after the discovery of the virus (4,16,20,23,49,71). Different steps of the virus cycle are sensitive to IFN (reviewed in references 24, 25, and 47).…”

mentioning

confidence: 99%

“…The inhibition of human immunodeficiency virus type 1 (HIV) replication by type I interferons (IFN) was demonstrated soon after the discovery of the virus (4,16,20,23,49,71). Different steps of the virus cycle are sensitive to IFN (reviewed in references 24, 25, and 47).…”

mentioning

confidence: 99%

Partial Inhibition of Human Immunodeficiency Virus Replication by Type I Interferons: Impact of Cell-to-Cell Viral Transfer

Vendrame

Sourisseau

Perrin

et al. 2009

J Virol

View full text Add to dashboard Cite

Type I interferons (IFN) inhibit several steps of the human immunodeficiency virus type 1 (HIV) replication cycle. Some HIV proteins, like Vif and Vpu, directly counteract IFN-induced restriction factors. Other mechanisms are expected to modulate the extent of IFN inhibition. Here, we studied the impact of IFN on various aspects of HIV replication in primary T lymphocytes. We confirm the potent effect of IFN on Gag p24 production in supernatants. Interestingly, IFN had a more limited effect on HIV spread, measured as the appearance of Gag-expressing cells. Primary isolates displayed similar differences in the inhibition of p24 release and virus spread. Virus emergence was the consequence of suboptimal inhibition of HIV replication and was not due to the selection of resistant variants. Cell-to-cell HIV transfer, a potent means of virus replication, was less sensitive to IFN than infection by cell-free virions. These results suggest that IFN are less active in cell cultures than initially thought. They help explain the incomplete protection by naturally secreted IFN during HIV infection and the unsatisfactory outcome of IFN treatment in HIV-infected patients.The inhibition of human immunodeficiency virus type 1 (HIV) replication by type I interferons (IFN) was demonstrated soon after the discovery of the virus (4,16,20,23,49,71). Different steps of the virus cycle are sensitive to IFN (reviewed in references 24, 25, and 47). IFN treatment of primary T lymphocytes, macrophages, and some T-cell lines efficiently inhibits early phases of infection, including HIVinduced cell fusion and reverse transcription (15,16,26,27,46,60,61,70). IFN also impair later steps of the HIV replication cycle, ranging from reduced virus protein processing and stability to altered virion release and composition (2,8,17,19,20,23,26,28,39,49,63,71,72). In these early reports, the experimental systems were optimized to measure the effect of IFN on either early or late steps of the virus replication cycle but did not fully explore the long-term efficacy of IFN.Some potential IFN-induced anti-HIV effectors were identified. Both the protein kinase R and the 2Ј,5Ј-oligoadenylate synthetase-directed RNase L pathways are activated by HIV components and may participate in the inhibition of HIV replication (32, 37, 59). IFN-␣ treatment also enhances the expression of TRIM5␣ and APOBEC3G (6, 53), two cellular factors that mediate potent intrinsic immunity against HIV and other viruses (reviewed in references 33 and 66). Moreover, recent studies have characterized IFN-induced antiviral factors that decrease virus particle release. In particular, IFN-stimulated gene 15 (ISG15) interferes with the recruitment of the cellular machinery required for viral assembly (43), TRIM22 appears to perturb virus precursor protein trafficking (3), and BST-2/CD317/HM1.24 (also called tetherin) acts by tethering mature virus particles to the cell surface (41, 67).HIV counteracts some of these antiviral systems, confirming that endogenous IFN exert a selective pressure...

show abstract

“…In vitro, type I IFN inhibits HIV-1 infection both at early steps of replication (24,25) and at the late steps of virus assembly and release (26)(27)(28). HIV-1 virions assembled in IFN-treated T cells show a low infectivity, accumulate at the plasma membrane, and have altered morphogenesis (29)(30)(31).…”

mentioning

confidence: 99%

Innate antiviral response targets HIV-1 release by the induction of ubiquitin-like protein ISG15

Okumura

Pitha-Rowe

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

318

277

View full text Add to dashboard Cite

The goal of this study was to elucidate the molecular mechanism by which type I IFN inhibits assembly and release of HIV-1 virions. Our study revealed that ISG15 was one of the first recognized ISGs (4). ISG15 is covalently conjugated to targeted proteins through a series of steps similar to ubiquitin conjugation. The ISG15 activating enzyme is ubiquitin E1 like protein (UBE1L), and the major E2 enzyme for ubiquitin conjugation, UbcH8, also recognizes ISG15 (5). An ISG15-specific ligase E3 has not yet been identified, but the IFN-induced Ub E3-like enzymes Rsp5 and CEB1͞Hc5 may function in ISG15 conjugation (6, 7). Like Ub (8), ISG15 is removed from conjugated proteins by an ISG15-specific protease, UBP43 (9). Interestingly, type I IFN stimulates expression not only of ISG15 but also UBEL1, UbcH8, and UBP43 (3, 10) and markedly increases ISG15 conjugation. ISG15 targets a large number of cellular proteins (7); however, modification by ISG15 does not typically cause substrate degradation (11).Ub is a central cellular regulator (12), and Ub-mediated proteolysis plays a regulatory role in the immune system (13). In general, polyubiquitination targets proteins toward 26S protease-associated degradation, whereas monoubiquitination is a signal for internalization and vesicle sorting. However, whereas polyubiquitination on lysine 43 targets proteins for degradation, lysine 63 polyubiquitination is a signal for kinase activation. Many viruses modulate the Ub-proteasome pathway to alter cellular signaling and the antiviral response (14, 15). HIV-1 uses ubiquitination at two steps of its replication cycle. First, HIV-1-encoded protein Vif targets cellular cytidine deaminase APOBEC3G for Ub mediated degradation, thus preventing APOBEC3G incorporation into viral particles and deamination of the viral genome during reverse transcription (16-18). Vif itself is monoubiquitinated and this may help its recruitment to the site of viral assembly (19). Second, ubiquitination of Gag by Ub ligase Nedd4.1 is critical for assembly and release of virions from infected cells (20). HIV-1 assembly is driven by the Gag poly protein (21), and deletion of the PTAP-L domain in p6 of Gag, or inhibition of the Gag interaction with Tsg101, a protein of the endosomal sorting complex (ESCRT-I) (22), results in accumulation of HIV-1 virions at the plasma membranes.An important role for type I IFN in the innate response to HIV-1 infection is suggested by the observation that deletion of high IFN producing dendritic pDC2 cells results in rapid progression of HIV-1 infection in vivo (23). In vitro, type I IFN inhibits HIV-1 infection both at early steps of replication (24,25) and at the late steps of virus assembly and release (26-28). HIV-1 virions assembled in IFN-treated T cells show a low infectivity, accumulate at the plasma membrane, and have altered morphogenesis (29)(30)(31). Similar defects were seen in IFN-treated cells infected with murine leukemia virus (32). We have shown that IFN-␣-and IFN-␤-mediated inhibition correlates with the induct...

show abstract

Inhibition of human immunodeficiency virus (HIV) replication by HIV-trans-activated alpha 2-interferon.

Cited by 85 publications

References 39 publications

Human Immunodeficiency Virus Viremia Induces Plasmacytoid Dendritic Cell Activation In Vivo and Diminished Alpha Interferon Production In Vitro

Human Immunodeficiency Virus Viremia Induces Plasmacytoid Dendritic Cell Activation In Vivo and Diminished Alpha Interferon Production In Vitro

Partial Inhibition of Human Immunodeficiency Virus Replication by Type I Interferons: Impact of Cell-to-Cell Viral Transfer

Innate antiviral response targets HIV-1 release by the induction of ubiquitin-like protein ISG15

Contact Info

Product

Resources

About