Relative resistance of HIV-1 founder viruses to control by interferon-alpha

Angharad E Fenton-May,Marlen M Aasa-Chapman,George M Shaw,John C Kappes,Haitao Ding,Tanja Emmerich,Myron S Cohen,Beatrice H Hahn,Ian Williams,Christina Ochsenbauer,Katja Pfafferott,Oliver Dibben,Feng Gao,Persephone Borrow,Pierre Pellegrino

doi:10.1186/1742-4690-10-146

Abstract

BackgroundFollowing mucosal human immunodeficiency virus type 1 (HIV-1) transmission, type 1 interferons (IFNs) are rapidly induced at sites of initial virus replication in the mucosa and draining lymph nodes. However, the role played by IFN-stimulated antiviral activity in restricting HIV-1 replication during the initial stages of infection is not clear. We hypothesized that if type 1 IFNs exert selective pressure on HIV-1 replication in the earliest stages of infection, the founder viruses that succeed in establishing systemic infection would be more IFN-resistant than viruses replicating during chronic infection, when type 1 IFNs are produced at much lower levels. To address this hypothesis, the relative resistance of virus isolates derived from HIV-1-infected individuals during acute and chronic infection to control by type 1 IFNs was analysed.ResultsThe replication of plasma virus isolates generated from subjects acutely infected with HIV-1 and molecularly cloned founder HIV-1 strains could be reduced but not fully suppressed by type 1 IFNs in vitro. The mean IC50 value for IFNα2 (22 U/ml) was lower than that for IFNβ (346 U/ml), although at maximally-inhibitory concentrations both IFN subtypes inhibited virus replication to similar extents. Individual virus isolates exhibited differential susceptibility to inhibition by IFNα2 and IFNβ, likely reflecting variation in resistance to differentially up-regulated IFN-stimulated genes. Virus isolates from subjects acutely infected with HIV-1 were significantly more resistant to in vitro control by IFNα than virus isolates generated from the same individuals during chronic, asymptomatic infection. Viral IFN resistance declined rapidly after the acute phase of infection: in five subjects, viruses derived from six-month consensus molecular clones were significantly more sensitive to the antiviral effects of IFNs than the corresponding founder viruses.ConclusionsThe establishment of systemic HIV-1 infection by relatively IFNα-resistant founder viruses lends strong support to the hypothesis that IFNα plays an important role in the control of HIV-1 replication during the earliest stages of infection, prior to systemic viral spread. These findings suggest that it may be possible to harness the antiviral activity of type 1 IFNs in prophylactic and potentially also therapeutic strategies to combat HIV-1 infection.

Highlights

Following mucosal human immunodeficiency virus type 1 (HIV-1) transmission, type 1 interferons (IFNs) are rapidly induced at sites of initial virus replication in the mucosa and draining lymph nodes
Establishment of an experimental system for evaluation of HIV-1 sensitivity to the antiviral activity of type 1 IFNs To quantitate the relative sensitivity of different HIV-1 isolates to type 1 IFN-mediated antiviral activity, we established an in vitro assay to evaluate the extent to which virus replication in activated CD4+ cells derived from the peripheral blood of HIV-seronegative donors was reduced by exposure of the cells to a range of concentrations of exogenously-added recombinant IFNα2 or IFNβ
Analysis of the sensitivity of virus isolates from patients acutely-infected with HIV to in vitro control by IFNα and IFNβ Virus isolates were generated from 11 patients presenting with symptomatic primary HIV-1 infection, all of whom were infected with clade B viruses, by coculture of plasma cryopreserved during acute infection with activated CD4+ cells derived from the peripheral blood of HIV-seronegative donors

Summary

Introduction

Following mucosal human immunodeficiency virus type 1 (HIV-1) transmission, type 1 interferons (IFNs) are rapidly induced at sites of initial virus replication in the mucosa and draining lymph nodes. Type 1 interferons (IFNs) are a family of innate cytokines that includes IFNβ and 13 subtypes of IFNα in humans They are constitutively produced at very low levels, but can be rapidly up-regulated in response to pathogen exposure or infection and play important effector and immunoregulatory roles in the early host immune response. Type 1 IFNs are highly pleiotropic innate cytokines that can contribute to viral containment by both direct and indirect mechanisms [8] Their importance in early viral control is indicated by the plethora of strategies that viruses have evolved to impair the production or activity of type 1 IFNs [9,10,11] and has been demonstrated experimentally using IFN-blocking antibodies and IFNα/β receptordeficient mice [12,13]. Chronic production of type 1 IFNs during persistent viral infections can have detrimental effects, driving hyperimmune activation and impairing control of ongoing viral replication [14,15]

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