Biomedical subjects

R J O Barnard

Publications and source records attributed to R J O Barnard.

3 recordsLinked to original sources

PubMed2006

Avian sarcoma and leukosis virus-receptor interactions: from classical genetics to novel insights into virus-cell membrane fusion.

For over 40 years, avian sarcoma and leukosis virus (ASLV)-receptor interactions have been employed as a useful model system to study the mechanism of retroviral entry into cells. Pioneering studies on this system focused upon the genetic basis of the differential susceptibilities of different lines of chickens to infection by distinct subgroups of ASLV. These studies led to the definition of three distinct autosomal recessive genes that were predicted to encode cellular receptors for different viral subgroups. They also led to the concept of viral interference, i.e. the mechanism by which infection by one virus can render cells resistant to reinfection by other viruses that use the same cellular receptor. Here, we review the contributions that analyses of the ASLV-receptor system have made in unraveling the mechanisms of retroviral entry into cells and focus on key findings such as identification and characterization of the ASLV receptor genes and the subsequent elucidation of an unprecedented mechanism of virus-cell fusion. Since many of the initial findings on this system were published in the early volumes of Virology, this subject is especially well suited to this special anniversary issue of the journal.

Animals↗

PubMed2004

Low pH is required for avian sarcoma and leukosis virus Env-induced hemifusion and fusion pore formation but not for pore growth.

Binding of avian sarcoma and leukosis virus (ASLV) to its cognate receptor on the cell surface causes conformational changes in its envelope protein (Env). It is currently debated whether low pH is required for ASLV infection. To elucidate the role of low pH, we studied the association between ASLV subgroup B (ASLV-B) and liposomes and fusion between effector cells expressing Env from ASLV-A and ASLV-B and target cells expressing cognate receptors. Neither EnvA nor EnvB promoted cell-cell fusion at neutral pH, but lowering the pH resulted in quick and extensive fusion. As expected for a low-pH-triggered reaction, fusion was a steep function of pH. Steps that required low pH were identified. Binding a soluble form of the receptor caused ASLV-B to hydrophobically associate with liposome membranes at neutral pH, indicating that low pH is not required for insertion of Env's fusion peptides into membranes. But both cell-cell hemifusion and fusion pore formation were pH dependent. It is proposed that fusion peptide insertion stabilizes the conformation of ASLV Env into a form that can be acted upon by low pH. At this point, but not before, low pH can induce fusion and is in fact required for fusion to occur. However, low pH is no longer necessary after formation of the initial fusion pore: pore enlargement does not require low pH.

Animals↗

PubMed2003

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.

Alpharetrovirus↗