Host and Viral Determinants of Interferon Resistance During HIV-1 Transmission

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Context. To sustain themselves, all viruses must be transmitted to a new host. Accordingly, strategies interfering with this stage of the viral lifecycle can have an enormous impact on human health, wellbeing and productivity. Interventions such as vaccination, basic hygiene, sterile medical devices and the screening of blood products have been hugely beneficial because they can prevent infection altogether (rather than treating an already infected patient). Thus, there is an urgent need to improve our understanding of virus transmission as this knowledge will underpin future strategies of viral infection prevention.Although effective HIV-1 treatments are available for those who can afford them, more than 2 million people become newly infected with HIV-1 every year worldwide. Infected patients can have more than a million HIV-1 virus particles in a single ml of blood. But even as viral loads can be high, the majority of new HIV-1 infections originate from infection by a single virus particle. There is great interest in understanding exactly why these particular particles are successfully transmitted, as interventions that specifically block transmission of these particles could prevent lifelong infection.Interferons are an early defence against invading pathogens that can signal infection and alert cells to increase the levels of their antiviral defences. Because these defences are increased in response to interferons, they are known as interferon-stimulated genes (ISGs). As a result of the hostile environment created by ISGs, most viruses (including HIV-1) are less able to replicate in the presence of interferons. However, unlike the average HIV-1 variant, the transmitted HIV-1 particles are far more resistant to interferon-mediated inhibition. This observation underpins the idea that host interferon responses are a substantial barrier to HIV-1 transmission, such that an HIV-1 variant that is interferon resistant is more likely to be successfully transmitted. Aims. Very little is known about which ISGs constrain HIV-1 transmission and how transmitted HIV-1 avoids this inhibition. Our overall aim is to illuminate the molecular details of this important and vulnerable stage of the HIV-1 lifecycle. We will do this by identifying: (i) the host factors that transmitted HIV-1 overcomes, and (ii) the mechanistic details that enable transmitted HIV-1 to resist interferon inhibition. To map the determinants of interferon resistance in transmitted HIV-1 particles, we will make hybrid viruses comprised of interferon sensitive and interferon resistant HIV-1 viruses, in order to locate the specific region(s) of HIV-1 that confer interferon resistance. We will also grow interferon sensitive HIV-1 in the presence of interferons, in order to learn how the virus adapts to this inhibition. We can then examine any identified resistance motifs in HIV-1 sequence data (from infected patients) to determine whether these motifs might influence HIV-1 transmission. To identify the host factors resisted by transmitted HIV-1 we will carry out screens to systematically measure the ability of hundreds of individual ISGs to inhibit HIV-1. Crucially, we will compare transmitted interferon resistant HIV-1 virus variants to interferon inhibited HIV-1 variants to identify ISGs that are specifically resisted by transmitted HIV-1.Applications and benefits. During the timeframe of this award we plan to illuminate an exciting area of HIV-1 biology and stimulate further research. In the longer term, our research defining the molecular details of HIV-1 transmission should aid the design of novel prevention/intervention strategies (such as vaccines) designed to target transmitted HIV-1. Furthermore, because sustainable transmission is an essential facet of pandemic viruses, the insight our work will provide on transmission of HIV-1 should improve our ability to assess the pandemic potential of other emerging viral pathogens.