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

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.

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

“…We previously reported that TF viruses are more resistant to IFNα2 than viruses from chronically infected individuals (26,52). However, two subsequent studies of linked transmission pairs failed to confirm this phenotype, with one study finding no differences in IFNα2 resistance between transmitted and nontransmitted viruses (27), and the other reporting transmitted viruses being more IFNα2 sensitive (28).…”

Interferon Alpha Subtype-Specific Suppression of HIV-1 Infection In Vivo

“…IFN-␣14 was 10.8-fold more potent (in picograms per milliliter), 13.6-fold more potent (in units per milliliter), and 11.0-fold more potent (nanomolar) than IFN-␣2. IFN-␣14 also inhibited HIV-1 with greater potency than IFN-␣2 at maximal IFN-␣ concentrations, as there was more residual HIV-1 replication (V res ) (45) in HIV-1-infected LPMCs treated with IFN-␣2 (V res ϭ 40%) versus IFN-␣14 (V res ϭ 30%). Based on these results, IFN-␣14 was selected for in vivo studies in HIV-1-infected humanized mice using the clinically approved IFN-␣2 subtype as the comparison control.…”

CD4 mimetics sensitize HIV-1-infected cells to ADCC

“…pNL43-ADA(Env)-GFP.IRES.Nef proviral vectors (deleted for vpu, nef, and nef and vpu or expressing the D368R Env variant) and the VSVG-encoding plasmid (pSVCMV-IN-VSV-G) were previously described (12,51). T/F and corresponding 6-mo consensus IMCs of patients CH58 and CH77 were inferred, constructed, and biologically characterized as described (36)(37)(38)(39).…”

“…To ensure that sensitization of HIV-1-infected cells by CD4 mimetics was also observed when using full-length clinically relevant primary HIV-1 isolates, we infected primary CD4 T cells with extensively characterized infectious molecular clones (IMCs) constructed from two transmitted/founder (T/F) and their corresponding 6-mo consensus sequences (36)(37)(38)(39). Primary viruses are known to exhibit low Env reactivity and, as such, have little or no intrinsic exposure of CD4i epitopes (40).…”