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

Abstract

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.

BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

“…IFN-␣ was then added to the cells at 1,000 U/ml. IFN-␤ (Rebif; EMD Serono Inc.) (19) was added to the cells at 1 ng/ml. IL-27 (R&D Systems) was reconstituted at 100 g/ml in sterile PBS containing 0.1% bovine serum albumin and stored at Ϫ80°C.…”

“…The antiviral effect exerted by IFN is highlighted by the observation that transmitted/founder HIV-1 strains that initiate host infection have been shown to be more resistant to type I IFN responses than HIV-1 strains found during the chronic phase of infection (17)(18)(19). Furthermore, Vpu enhances viral replication particularly during early stages of infection, probably by counteracting the IFN-inducible restriction factor BST-2 (18,20).…”

The HIV-1 transmission bottleneck

“…A recent study by Iyer and co-authors [160] circumvented these problems by generating 300 single genome viral isolates using limiting dilution from transmission pairs. Isolates were from plasma and genital secretions of chronically infected donors and from plasma of their matched recipients.…”

TLR3 agonism re‐establishes CNS immune competence during α4‐integrin deficiency

“…However, natalizumab has since been used exclusively as monotherapy, and any potential beneficial effect of IFN β has therefore never been studied. As stated above, there are other type I IFNs, including IFN α , IFN κ , IFN ω , of which IFN α appears to have the most potent anti‐viral properties 15, 16, 17. Secondly, there are pharmacological limitations.…”