Antithetic effect of interferon-alpha on cell-free and cell-to-cell HIV-1 infection

摘要

Author summaryHIV-1 experiences a strong bottleneck during transmission, and only the virus(es) with higher resistance to the host's innate immunity, interferon (IFN), can be successfully transmitted. Because the IFN resistance tends to be disappeared during infection in infected individuals, this phenotype would be crucial for human-to-human transmission. By combining mathematical modeling with well-designed time-series viral infection experiments, we investigated the difference on the IFN resistance of two types of HIV-1, which were respectively isolated at the acute and chronic phases of infection, and classified it into two virus transmission modes, cell-free and cell-to-cell infections. We found that IFN suppresses HIV-1 cell-to-cell infection, but surprisingly, promotes cell-free infection. Moreover, the virus isolated during chronic infection is more sensitive to the IFN-mediated promoting effect than that isolated during acute infection. Our results suggest that HIV-1 selects different strategies to adapt to different host environments. We further provide an insight how viruses evolve to counteract or hijack the host immunity. In HIV-1-infected individuals, transmitted/founder (TF) virus contributes to establish new infection and expands during the acute phase of infection, while chronic control (CC) virus emerges during the chronic phase of infection. TF viruses are more resistant to interferon-alpha (IFN-alpha)-mediated antiviral effects than CC virus, however, its virological relevance in infected individuals remains unclear. Here we perform an experimental-mathematical investigation and reveal that IFN-alpha strongly inhibits cell-to-cell infection by CC virus but only weakly affects that by TF virus. Surprisingly, IFN-alpha enhances cell-free infection of HIV-1, particularly that of CC virus, in a virus-cell density-dependent manner. We further demonstrate that LY6E, an IFN-stimulated gene, can contribute to the density-dependent enhancement of cell-free HIV-1 infection. Altogether, our findings suggest that the major difference between TF and CC viruses can be explained by their resistance to IFN-alpha-mediated inhibition of cell-to-cell infection and their sensitivity to IFN-alpha-mediated enhancement of cell-free infection.