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This starter grant funded studies aimed at identifying and characterizing cellular factors that either inhibited HIV-1 replication, or were required by the virus to facilitate its replication. In the first aim we focused on the antiviral factor tetherin/BST2 that we had previously identified, which is the target for the accessory viral protein Vpu. In particular, we aimed to determine how tetherin’s antiviral activity may augment the immune recognition of an infected cell. We found that when tetherin restricts HIV-1 (and other virus) release it transduces a proinflammatory signal in the infected cell, inducing cytokine expression that makes the infected cell more visible to the wider immune response. We characterized the mechanism of this signal transduction, determining how virus release was ‘sensed’ by tetherin through its linkage to the underlying cytoskeleton via an adaptor protein, RICH2, and the activation of Src-family kinases. We further showed how this activity was mammalian species specific and found evidence highly suggestive that tetherin’s signaling capacity had a selective pressure on the adaptation of HIV-1 Vpu in humans, thought to be a key event in the pandemic spread of the virus. We also further characterized the cellular mechanism of Vpu in counteracting tetherin, in particular showing how its phosphorylation regulated interaction with clathrin adaptor proteins and prevention of tetherin’s trafficking to the plasma membrane. In studying Vpu function in patients, we have also made the observation that primary alleles are very potent inhibitors of proinflammatory signaling, and have amassed much preliminary data that indicates the molecular basis for this enhanced activity. These studies have formed the basis for funding application to the MRC.

In addition to Vpu/tetherin, we have investigated the role of the HIV-1 protein Vpr, whose biological function remains unclear. We have been able to show that Vpr, which is packaged into the virus particle, potently shuts down pattern recognition signaling in the infected cell during the early stages of viral replication. We have embarked on various proteomic approaches to identify the relevant targets of Vpr that might explain this activity. Our initial evidence suggests a novel Vpr target associated or proximal to the nuclear membrane is a likely candidate, and we are characterizing this factor for publication soon. Such a factor will have important implications for the pathogenesis of HIV/AIDS and in general for understanding how pattern recognition signaling in the innate immune system is propagated.

Finally, we have made important observations about the role of a family of antiviral membrane proteins, IFITMs, that inhibit HIV-1 entry. We found that transmitted strains of HIV-1 are under pressure to be resistant to these factors, but that adaptations in the envelope glycoprotein in the months after infection that resist adaptive immune responses develop IFITM sensitivity. This is linked to differences in the cell biology of how HIV-1 enters its target cells. These data have important implications for the constraints on the HIV-1 Env at transmission of relevance on vaccine/inhibitor design. These studies and those on Vpr have formed the basis of further funding applications to the Wellcome Trust.