Alpharetrovirus Envelope-Receptor Interactions

Infection by all enveloped viruses occurs via the fusion of viral and cellular membranes and delivery of the viral nucleocapsid into the cell cytoplasm, after association of the virus with cognate receptors at the cell surface. This process is mediated by viral fusion proteins anchored in the viral envelope and can be defined based on the requirement for low pH to trigger membrane fusion. In viruses that utilize a pH-dependent entry mechanism, such as influenza virus, viral fusion is triggered by the acidic environment of intracellular organelles after uptake of the virus from the cell surface and trafficking to a low-pH compartment. In contrast, in viruses that utilize a pH-independent entry mechanism, such as most retroviruses, membrane fusion is triggered solely by the interaction of the envelope glycoprotein with cognate receptors, often at the cell surface. However, recent work has indicated that the alpharetrovirus, avian sarcoma and leukosis virus (ASLV), utilizes a novel entry mechanism that combines aspects of both pH-independent and pH-dependent entry. In ASLV infection, the interaction of the envelope glycoprotein (Env) with cognate receptors at the cell surface causes an initial conformational change that primes (activates) Env and renders it sensitive to subsequent low-pH triggering from an intracellular compartment. Thus unlike other pH-dependent viruses, ASLV Env is only sensitive to low-pH triggering following interaction with its cognate receptor. In this manuscript we review current research on ASLV Env-receptor interactions and focus on the specific molecular requirements of both the viral fusion protein and cognate receptors for ASLV entry. In addition, we review data pertaining to the novel two-step entry mechanism of ASLV entry and propose a model by which ASLV Env elicits membrane fusion.