Richard S. B. Milne

Human immunodeficiency virus (HIV) is an exemplar virus, still the most studied and best understood and a model for mechanisms of viral replication, immune evasion and pathogenesis. In this review, we consider the earliest stages of HIV infection from transport of the virion contents through the cytoplasm to integration of the viral genome into host chromatin. We present a holistic model for the virus–host interaction during this pivotal stage of infection. Central to this process is the HIV capsid. The last 10 years have seen a transformation in the way we understand HIV capsid structure and function. We review key discoveries and present our latest thoughts on the capsid as a dynamic regulator of innate immune evasion and chromatin targeting. We also consider the accessory proteins Vpr and Vpx because they are incorporated into particles where they collaborate with capsids to manipulate defensive cellular responses to infection. We argue that effective regulation of capsid uncoating and evasion of innate immunity define pandemic potential and viral pathogenesis, and we review how comparison of different HIV lineages can reveal what makes pandemic lentiviruses special.

Tetherin is a broadly active antiviral effector that works by tethering nascent enveloped virions to a host cell membrane, thus preventing their release. In this study, we demonstrate that herpes simplex virus 1 (HSV-1) is targeted by tetherin. We identify the viral envelope glycoprotein M (gM) as having moderate anti-tetherin activity. We show that gM but not gB or gD efficiently removes tetherin from the plasma membrane and can functionally substitute for the human immunodeficiency virus type 1 (HIV-1) Vpu protein, the prototypic viral tetherin antagonist, in rescuing HIV-1 release from tetherin-expressing cells. Our data emphasize that tetherin is a broadly active antiviral effector and contribute to the emerging hypothesis that viruses must suppress or evade an array of host cell countermeasures in order to establish a productive infection.