Mathieu Dubé Talks about the Role of Tetherin in HIV Research

New Hot Paper Commentary, July 2011

Mathieu Dubé

Article: Antagonism of Tetherin Restriction of HIV-1 Release by Vpu Involves Binding and Sequestration of the Restriction Factor in a Perinuclear CompartmenT

Authors: Dube, M;Roy, BB;Guiot-Guillain, P;Binette, J;Mercier, J;Chiasson, A;Cohen, EA
Journal: PLOS PATHOG, Volume: 6, Issue: 4, Page: art., Year: no.-e1000856 APR 2010
* Inst Rech Clin Montreal, Lab Human Retrovirol, Montreal, PQ H2W 1R7, Canada.
(Addresses have been truncated)

Mathieu Dubé talks with and answers a few questions about this month's New Hot Paper in the field of Microbiology.

SW: Why do you think your paper is highly cited?

After 15 years without significant progress, the discovery of Tetherin in 2008 was a major breakthrough in the field of HIV research. Indeed, it paved the way towards a better understanding of the mechanisms by which Vpu increases the release of HIV-1 viral particles from infected cells. Enthusiasm spread quickly with numerous papers pertinent to Tetherin published between 2008 and 2010. Nevertheless, although each of them contributed a piece, the puzzle remained incomplete.

Our work, performed in this context, might be a first attempt to integrate these eclectic studies in a single comprehensive model. In the chaotic debut of the research on Tetherin, our work perhaps serves as the needed consensus to pursue further studies on the subject. Indeed, this would not have been possible without the tremendous efforts of other groups.

SW: Does it describe a new discovery, methodology, or synthesis of knowledge?

Our study complemented two years of knowledge with our own observations. Basically, we compared previously suggested mechanisms and evaluated their relative contributions to the antagonism of Tetherin by Vpu. We sought to clarify the numerous discrepancies among the studies trying to unravel the mechanism by which Vpu antagonizes Tetherin.

We addressed this challenge by employing existing and proven techniques. Why invent something new when the needed tools are already available? This thinking may explain our use of old-school techniques as well as forgotten ageing methods rather than adopting recent and popular high-tech innovations.

SW: Would you summarize the significance of your paper in layman's terms?

HIV-1 Vpu, as other HIV-1 non-structural accessory proteins, was well known to hijack cellular machineries, thus manipulating the cell environment to the benefit of the virus. This viral protein was shown earlier on to recruit SCFß-TrCP, an enzymatic complex involved in the degradation of several cellular proteins, to mediate the degradation of CD4, the protein used by HIV-1 to enter the cell. This chain of events was later shown to avoid superinfection or interference with the trafficking of the CD4-interacting HIV-1 envelope glycoprotein trafficking towards the cell surface. However, although suggested by some, it was not clear if such a degradative process would also be involved during Tetherin antagonism.

"I may be over-optimistic given my interest on the protein, but I am convinced that such an anti-Vpu drug therapy might include a pharmacological target aiming at the domain of interaction with Tetherin, shared with other of its substrates..."

Early reports showed that cell-surface Tetherin was downregulated by Vpu. Initially, this process was automatically linked to recruitment of SCFß-TrCP by Vpu. Although this assumption appeared true at the first glance, it also introduced a bias that drifted the field in a wrong direction. Indeed, we discovered that antagonism of Tetherin by Vpu can be achieved even without the recruitment of SCFß-TrCP or Tetherin degradation through a mechanism involving intracellular sequestration within an organelle called the trans-Golgi network, resulting in insufficient levels of this restriction factor at the cell-surface to trap progeny viruses.

As a consequence, we believe that our discovery has perhaps reoriented further studies towards the trafficking of Tetherin in the presence of Vpu rather than its degradation. We also mapped the regions of the two proteins responsible for their mutual interaction, which appeared crucial for the sequestration. We hope that this information will facilitate the elaboration of strategies aiming at disturbing Vpu functions.

SW: How did you become involved in this research, and how would you describe the particular challenges, setbacks, and successes that you've encountered along the way?

Many previous reports made use of overexpression systems of Tetherin and Vpu which ease investigation and analysis. However, since the levels of proteins made in these systems are generally much higher than physiological levels, one should exercise caution when interpreting the conclusions arising from those studies.

In our investigation, we decided to study endogenous Tetherin, the one that is naturally produced in cells, and to express the Vpu protein from an infectious clone of HIV-1 instead of using a Vpu-expressor plasmid. Our systems may not be as straightforward as the overexpressing systems and may require a great deal of efforts, but they are more physiologically relevant and easier to extrapolate to a productive viral infection. At the end of the day, our strategy proved to be successful since we discovered a mechanism of antagonism not identified in systems of overexpression.

SW: Where do you see your research leading in the future?

Things are moving fast in HIV-1! It is difficult to say. Indeed, mapping the interaction site of Tetherin and Vpu transmembrane domains would be important in the development of novel approaches targeting Vpu. However, this is not for tomorrow since the implication of Tetherin antagonism by Vpu during HIV-1 pathogenesis is not yet clear. I assume that our actual model will be improved sooner or later—probably sooner—as research on this small protein is continuing.

What we did not expect is that our work also serves as a model for a growing list of Vpu substrates. Now, it will be interesting to assess whether Vpu acts on a general trafficking pathway to affect these numerous cellular targets. This would be a major discovery for both cell biologists and virologists paving the way towards new anti-HIV-1 strategies.

SW: Do you foresee any social or political implications for your research?

This is a difficult question. If our work has any social implications, it would probably be in the long term. HIV-1 research is strongly influenced by the need for new anti-retroviral drugs. Up to now, accessory proteins have not been considered good targets since their roles in viral replication and pathogenesis remain incompletely characterized.

Nevertheless, given the current known functions of Vpu and the fact that accessory proteins are increasingly recognized as modulators of the host immune system, one may expect that a focus of future studies would be on devising ways to minimize Vpu effects. Indeed, my fundamental research, like any other recently performed on Vpu, was pursued with the hope of defining the best strategy to interfere with Vpu function.

I may be over-optimistic given my interest on the protein, but I am convinced that such an anti-Vpu drug therapy might include a pharmacological target aiming at the domain of interaction with Tetherin, shared with other of its substrates. Whether this will occur before another therapy circumvents AIDS is another question....Time will tell us.End

Mathieu Dubé
Ph.D. candidate
Laboratory of Human Retrovirology
Institut de recherches cliniques de Montréal
Montréal, QC, Canada



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