CROI: Tetherin: a newly discovered host cell protein that inhibits HIV replication

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In a Wednesday morning plenary session at the 15th Conference on Retroviruses and Opportunistic Infections, Paul Bieniasz of the Aaron Diamond AIDS Research Center gave an overview of research findings in the area of retrovirus/host cell interactions. Notably, a human cellular protein has recently been identified which prevents newly formed viral particles from being fully released from infected cells.

In the context of viral infections, infected cells are known as host cells due to the host role they play to the infectious agents. The research field of viral/host cell interactions investigates the ways in which host cells' innate defensive mechanisms interact with viral infectious processes.

Host cells in humans and other primates have evolved a number of proteins that inhibit retroviral infection and replication. Genetic evidence indicates that these defensive proteins are produced by genes that have evolved over a very long time, and were shaped by ancient retrovirus epidemics. Since retroviruses evolve much more quickly than primates, these genetic defenses may be only partly or poorly effective against modern-day retroviruses such as HIV.

Glossary

protein

A substance which forms the structure of most cells and enzymes.

retrovirus

A type of virus that uses of RNA as its genetic material. After infecting a cell, a retrovirus uses an enzyme called reverse transcriptase to convert its RNA into DNA (the hereditary material in humans). The retrovirus then integrates its viral DNA into the DNA of the host cell, which allows the retrovirus to replicate. HIV is a retrovirus. 

replication

The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

host cell

A host cell is a living cell invaded by, or capable of being invaded by, an infectious agent (such as a bacterium or a virus).

 

gene

A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.

Several antiviral host cell proteins are currently the subjects of research. One such protein, TRIM5, is able to recognize retroviral capsid proteins in infected cells and inactivate the retrovirus by an as yet unknown process. Another, APOBEC3, infiltrates newly produced viruses and degrades their genetic material.

HIV, however, has evolved ways to counter the actions of these proteins. These viral countermeasures are often driven by so-called viral accessory genes such as vif and vpu. These genes – unlike those that code directly for reverse transcriptase and other essential parts of the replication cycle – are not directly involved in viral replication, and their purpose was at first not clearly understood. It is now becoming clear that they play a key role in evading cellular defenses.

HIV can resist the effects of TRIM5 by varying the sequence of its capsid proteins, or by binding a host cell protein called cypA to TRIM5. The viral vif gene produces a protein which prevents APOBEC from being incorporated into new viruses.

Tetherin and the vpu gene

The remainder of the plenary focused on a third antiviral process in host cells that is only now being more clearly defined, after a long period of research into the function of the viral vpu gene which produces the Vpu protein.

Certain host cells are known to have a means of inhibiting the release of newly formed retrovirus particles. Not all host cells show this activity. In those that do, HIV that has had Vpu removed cannot replicate – indicating that Vpu plays a part in the release of new viral particles.

Several lines of evidence have shown that cells which can inhibit the release of new virions do so by using cell proteins which bind newly formed retroviruses to the cell surface. In cells which are actively expressing these proteins (dubbed "tetherins"), newly budded virions can be seen to cluster densely just outside the cell membrane and remain there, rather than being released into the body to serve as new infectious particles.

This "tethering" action is opposed by the HIV accessory protein, Vpu. Vpu is otherwise not strictly needed for viral replication, and its function was originally poorly understood; it is now recognized as a viral countermeasure against cells which produce tetherin.

In the last several months, independent studies at Bienasz's lab and that of John Guatelli of the University of California, San Diego have both identified a specific protein (cellular transmembrane protein BST-2/CD317) that appears to play this tethering role. Cells that express this protein – dubbed tetherin – are able to inhibit HIV viral release. These same cells become permissive of viral release when this protein is removed. HIV lacking the vpu gene is not able to successfully bud from these cells when they are actively producing this protein, but can do so when its production is shut down.

Tetherin has been observed to block the release of retroviruses other than HIV, and is triggered by the presence of the inflammatory cytokine interferon-alpha which is released by the immune system during viral infections.

While there are no immediate therapeutic implications, Bieniasz concluded by noting that future work will continue to explore the spectrum of viruses against which tetherin is active, the precise mechanisms by which tetherin inhibits viral replication, and the mechanisms by which the HIV Vpu protein opposes tetherin. The complexity of this area of HIV/host cell interaction could ultimately provide new avenues for therapeutic interventions; conceivably, for example, small drug molecules might be designed which could inhibit the action of viral Vpu.

References:

Bieniasz P. New insights into retrovirus-host-cell interactions. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 114, 2008.

Guatelli J, Goff D and Van Damme N. Modulation of viral assembly and virion release by Vpu. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 104a, 2008.