A visit to the current controversy: manmade mutant H5N1 influenza virus (1)

A researcher, named Ron Fouchier, claimed that he has created a new variant (or you may call it the mutant) of H5N1 influenza virus. Normally, H5N1 influenza virus can not be transmitted between human and human. And it rarely transmits from an avian source to human. But when it does, the fatality rate is approximately 50%. Dr. Fouchier, who is an investigator at the Erasmus Medical Center in the Netherlands, claimed that he has created a new and airborne H5N1 influenza virus. This mutant is transmissible between mammals. Although his research finding is yet published and opened to the public, his research has created a controversy in the balance of academic freedom and protecting the nation from bioterrorism. As a member of the general public, I, too, have no idea what the introduced mutation Dr. Fouchier made to the original H5N1 strain. As a nascent virologist here at UC, here I will make some speculation and discuss about the ongoing situation.

Redefining the risk of mutant virus

One of the key aspects circulating in the news is the fact that this mutant is “airborne”. In my opinion, almost all viruses that disseminate within the respiratory tract are airborne. If viruses are able to replicate in our lung, it is highly possible that the mucus or droplets from an infected individual contain a considerable amount of viruses. The reason why some viruses is not able to disseminate effectively is possibly due to the failure to replicate efficiently within the host, resulting in a low concentration/titer of viruses which may not be enough to infect another susceptible individual.

“TONY EASTLEY: Scientists who have produced an airborne mutated of the killer bird flu virus H5N1 say it’s essential their research be published, but opponents say the biosecurity risks are too high and would be a “how to” manual for terrorists.” ABC NEWS

The public is now informed that this mutant virus is airborne. But honestly, the concern should be focus on the fact that it has now adapted to be spread between human and human. In the past, humans are the accidental host of H5N1 viruses. In other words, it is rare when the H5N1 viruses infect humans. So the concern should focus on the fact that the specific mutation can change the targeting species and disseminating efficiency. For an effective virus replication cycle, the virus must find a susceptible host cell that expresses a certain protein on its membrane. These proteins are known as receptors. These receptors are the key for the virus to recognize the proper cells to enter. The next barrier the virus needs to overcome is whether the host cells can provide the necessary factors for it to replicate.

In the next issue, we will continue to discuss how the viral surface proteins can be mutated to recognize different hosts (which I think it’s one of the key barriers to derive a new species in viruses). We will go over some current literature on CHIKV mutation and how the mutation on the viral surface protein can change the selectivity and the replication efficiency.

Reference:

http://www.nature.com/news/mutant-flu-researcher-plans-to-publish-even-without-permission-1.10469

http://www.abc.net.au/am/content/2012/s3451837.htm

http://journalism.berkeley.edu/projects/worldandus/archives/2005/11/avian_flu_and_a.php

http://www.nytimes.com/2012/03/06/health/amateur-biologists-are-new-fear-in-making-a-mutant-flu-virus.html?pagewanted=all

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A recurring theme: virus exploits the host’s machinery.

One of the most fascinating thing I found associated with all types of viruses is that they are capable of hijacking cellular machinery with only a few genes. In the case of dengue virus (DENV), it only codes for 7 nonstructural and 3 structural genes. And how these tiny viruses can take over host cells of about 20000-25000 genes is just fascinating. I attended a seminar, called “The ESCRT pathway in HIV budding and cell division” today down at GCIS. It was hosted by Dr. Wesley Sundquist from University of Utah (shown right). And here, I will talk about what the major concepts mentioned in the talk.

ImageAccording to wikipedia, “ESCRT (endosomal sorting complex required for transport) refers to a series of cytosolic protein complexes called ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III.” There are 3 major roles of ESCRT machinery: (1) multivesicular bodies (MVB) formation, (2) virus budding, and (3) cytokinesis. The MVB formation is important in recycling receptors that are endocytosed into the cells. One of the prime examples is the EGF receptor that gets endocytosed after binding to the EGF molecules. After the EGFR is internalized in the lysosome, it is then localized in the MVB to traffick to the endosomes for ubiquitination, which is then expressed on the cell surface for another round of binding to EGFR. In the case of cytokinesis, ESCRT-III forms a multimer around the midbody between two daughter cells (in other words, it wrap around the junction between two daughter cells). Then, an ATPase interacts with ESCRT-III to facilitate the cleavage and separate the two daughter cells. (it is likely that this ATPase contribute a conformational change to the ESCRT-III proteins, which give rise to enough thermal energy to break apart the junction.

HIV exploits this pinching technique by ESCRT-III to bud off from the host cells. It was shown that the envelope protein, Gag, interacts with ALIX. ALIX then interacts with ESCRT-III, which then Vps4 ATPase comes in to facilitate the pinching. As a result, progeny HIV can then be released from the host cells to continue infect neighboring uninfected cells. In the case of ALIX-depleted (siRNA-ALIX treated) cells (see below), HIV is not able to bud well from the host cell, and there is some distinguishable difference in the envelope of the HIV between the wildtype HIV and ALIX binding site mutant HIV.

Taken together, HIV exploits the cellular cleavage mechanism used for cytokinesis to facilitate its budding from the host.

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Summary:

– Virus exploits cellular pathways to facilitate its replication cycle

– Cellular ESCRT pathway is important for HIV budding.

References:

Fujii et al. Freed, Functional role of Alix in HIV-1 replication, Virology, Volume 391, Issue 2, 1 September 2009, 284-292, J. Virol.

Wollert et al. The ESCRT machinery at a glance. July 1, 2009 J Cell Sci 122, 2163-2166.

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