Binding and activity of all human alpha interferon subtypes

Lavoie, Thomas B.; Kalie, Eyal; Crisafulli-Cabatu, Sara; Abramovich, Renne; DiGioia, G. A.; Moolchan, Karlene; Pestka, Sidney; Schreiber, Gideon

doi:10.1016/j.cyto.2011.07.019

Cited by 162 publications

(193 citation statements)

References 24 publications

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“…This observation is consistent with previous studies showing that innate responses in the mucosa immediately following infection are inducing a potent antiviral state through the up-regulation of ISGs, many of which have anti-HIV-1 activity (63,64,(66)(67)(68)(69)(70)(71)(72)(73). All IFN subtypes signal through the same heterodimeric receptor (30), but differences in receptor binding and/or downstream signal transduction pathways are thought to be responsible for IFN subtype-specific biological effects (74)(75)(76)(77). IFNβ has been reported to bind the IFN receptor (IFNAR) with the highest affinity (76) and ligates the IFNAR1 chain in an IFNAR2-independent manner, resulting in the expression of a distinct set of genes (78).…”

Section: Discussionsupporting

confidence: 80%

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Iyer

Bibollet-Ruche

Sherrill-Mix

et al. 2017

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

132

180

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Sexual transmission of HIV-1 is an inefficient process, with only one or few variants of the donor quasispecies establishing the new infection. A critical, and as yet unresolved, question is whether the mucosal bottleneck selects for viruses with increased transmission fitness. Here, we characterized 300 limiting dilution-derived virus isolates from the plasma, and in some instances genital secretions, of eight HIV-1 donor and recipient pairs. Although there were no differences in the amount of virion-associated envelope glycoprotein, recipient isolates were on average threefold more infectious (P = 0.0001), replicated to 1.4-fold higher titers (P = 0.004), were released from infected cells 4.2-fold more efficiently (P < 0.00001), and were significantly more resistant to type I IFNs than the corresponding donor isolates. Remarkably, transmitted viruses exhibited 7.8-fold higher IFNα2 (P < 0.00001) and 39-fold higher IFNβ (P < 0.00001) half-maximal inhibitory concentrations (IC 50 ) than did donor isolates, and their odds of replicating in CD4 + T cells at the highest IFNα2 and IFNβ doses were 35-fold (P < 0.00001) and 250-fold (P < 0.00001) greater, respectively. Interestingly, pretreatment of CD4 + T cells with IFNβ, but not IFNα2, selected donor plasma isolates that exhibited a transmitted virus-like phenotype, and such viruses were also detected in the donor genital tract. These data indicate that transmitted viruses are phenotypically distinct, and that increased IFN resistance represents their most distinguishing property. Thus, the mucosal bottleneck selects for viruses that are able to replicate and spread efficiently in the face of a potent innate immune response.

show abstract

Section: Discussionsupporting

confidence: 80%

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Iyer

Bibollet-Ruche

Sherrill-Mix

et al. 2017

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

132

180

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“…It is becoming apparent that subtle differences in the amino acid sequences of IFN-␣ subtypes can produce a significant effect on the binding affinity for the IFN-␣/␤ receptor, downstream signaling events, and antiviral efficacy (2)(3)(4)(5)82). Given that rhesus macaque IFN-␣2 sequences compared to human and SM/AGM IFN-␣2 are only 92 and 98% identical, respectively, future studies in macaques should consider using species-specific IFNs rather than human IFNs (83).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, human IFN-␣ is not a single entity, but rather, the products of a multigene family encoding 12 IFN-␣ subtypes (1), all of which bind to the IFN-␣/␤ receptor. Each subtype binds the receptor using distinctive contacts (2), thereby eliciting distinct signaling events (3,4) and variable biological outcomes (5). While the unique affinity of the subtypes for each receptor subunit seems to contribute to differential downstream signaling, there appear to be additional factors influencing the unique outcomes elicited by individual subtypes that are currently not fully understood.…”

mentioning

confidence: 99%

Interferon Alpha Subtype-Specific Suppression of HIV-1 InfectionIn Vivo

Lavender¹,

Gibbert

Peterson³

et al. 2016

J Virol

112

188

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“…The subtleties that govern these responses remain unclear (27)(28)(29)(30)(31). Sequence alignment of mIFNε with mIFNβ, mIFNα1 and hIFNα2 reveals the degree of homology of the IFNs within the known IFNAR1 and IFNAR2 binding interfaces, suggesting differences in the way these IFNs might interact with their receptors ( Supplementary Fig S3).…”

Section: Discussionmentioning

confidence: 99%