Abstract Body

Background: Understanding host mechanisms of immune control of HIV-1 replication during the earliest stages of infection prior to systemic virus dissemination constitutes a key first step in the rational development of novel strategies to limit virus transmission. Production of type 1 interferons (IFNs), pleiotropic innate cytokines that mediate direct antiviral activity and exert a multitude of immunoregulatory effects, is one of the earliest innate responses triggered during many virus infections. Although type 1 IFNs are known to be produced at initial sites of HIV-1 replication in the mucosa and draining lymph nodes, their role in restricting early HIV-1 replication and the mechanisms by which they mediate their antiviral activity are poorly understood. We recently demonstrated that transmitted-founder (TF) viruses are more resistant to control by IFN-alpha than viruses present in the same subjects during early chronic infection, when type 1 IFNs are produced at much lower levels. This suggests that type 1 IFNs exert selective pressure on HIV-1 replication at initial infection sites, resulting in establishment of systemic infection by relatively IFN-resistant viruses. Here, this hypothesis was explored further by studying the relative IFN resistance of viruses from a virologically-linked transmission pair. Matched pairs of TF and 6-month consensus infectious molecular clones were also used to explore the genetic basis of the IFN-alpha resistance of TF viruses and the interferon-stimulated genes (ISGs) exerting selective pressure on HIV-1 transmission. Conclusions: Together, our results support an important role for type 1 IFN-mediated antiviral activity in restricting HIV-1 replication at initial infection sites, resulting in preferential establishment of systemic infection by relatively IFN-resistant viral variants. The IFN resistance of TF viruses typically declines within the first 6 months of infection. Viruses from different subjects lose resistance to different interferon-stimulated genes during early infection, suggesting that multiple antiviral ISGs contribute to restriction of HIV-1 transmission.