BDV infects many bird and mammal species, causing a severe neurological disorder, but does not usually infect mice. However, virus extracted from monkey cells grown in the lab can be injected into rat brain, where it will cause disease symptoms within a few weeks. Extracts from the rat's brain can then be injected into mice, which will display some signs of neuronal infection, but no symptoms. Extracts from the mouse brains are then injected into new mice, and so on until the virus eventually evolves to become infectious and pathogenic in the mouse host.

To determine how this process happens, Ackermann et al. sequenced the genomes of viruses that had successfully adapted to mouse hosts. They found three point mutations (single-letter typos) that were each present in around 80 – 100% of evolved viruses. The mutations mapped to proteins within the polymerase complex that is responsible for transcribing the viral genes into RNA. Two of the mutations arose twice independently, indicating that they confer a strong selective advantage to viruses that are in the process of adaptation to mouse cells.

The researchers engineered viruses that contained either a single mutation, or a combination of two or three of the original mutations. The mutated viruses were then put through their paces in a series of tests for replication in cultured cells and in living mouse brains. While each mutation individually improved the ability of BDV to infect mouse cells, the viruses that combined two or three different mutations grew the most aggressively. Not surprisingly, the viruses that multiplied the fastest caused the most severe symptoms in infected mice.

So how do polymerase mutations enable BDV to infect mice? One possible mechanism is interference with the normal interactions between different members of the polymerase protein complex. Indeed, one of the evolved changes essentially blocked the mutated protein subunit from binding to a partner that usually inhibits polymerase activity. The result is increased transcription of the viral RNA, which appears to be enough to overcome the mouse cell's normal barriers to BDV infection. This is not the only route by which viruses can evolve new host specificities, but it is certainly an effective one.

The second paper is from the same issue of the Journal of Virology, and involves host resistance to HIV. Lokesh Agrawal, from the Indiana University School of Medicine, worked with colleagues in China and France to study why some Caucasians are resistant to HIV infection, and how that resistance can sometimes fail.

The first thing that HIV needs to do before infecting a cell is to bind to its surface. This requires the presence of two proteins on the cell's surface membrane – CD4, and usually CCR5 (R5) or CXCR4 (X4). In other words, the virus needs to fit keys into two different locks in order to enter the cell. Some Caucasians carry a mutation in R5 that prevents the protein from reaching the cell surface and contacting the virus; one of the two locks closes, and the virus can not enter. Around 1% of the Caucasian population have two copies of the mutated R5 protein, and therefore have no R5 protein on the surface of their cells. HIV infection is very rare in these individuals, but a few cases are known. Agrawal and colleagues wanted to know how these patients' usual defenses had failed.

The first phase of the study examined the amount of R5 and X4 cell surface protein expression on the surface of cells from various individuals. HIV negative subjects with 2 mutated copies of R5 (known as R5-/-) did not express R5 on the surface of their cells, as expected. They also expressed X4 less strongly than normal, presumably because the mutated R5 protein is known to bind X4 and hold it captive inside the cell, preventing it from reaching the surface. This represents a double line of defense against both R5- and X4-specific viral strains. However, HIV positive R5-/- patients expressed normal levels of X4 on their cell surfaces, suggesting that HIV infection somehow prevents the mutated R5 protein from retaining the X4 protein inside the cell. The researchers showed that the increased level of surface X4 protein made HIV positive R5-/- cells more susceptible to viral cell penetration.

As expected, cells that contained more copies of the mutated R5 protein were generally the most resistant to HIV infection. However, the stability of the mutant protein also played an important role. Some HIV positive R5-/- patients' cells remained susceptible to viral entry despite artificially increasing their level of mutated R5 protein expression, as the protein was too short-lived to perform its usual protective function. The paper's discussion section speculates on several potential mechanisms by which HIV infection could destabilise the mutated R5 protein, and hence reopen the X4 lock to allow viral cell entry. One such mechanism is targeted destruction of the mutated R5 protein by Tat, a viral protein that is known to increase the expression of X4. The authors look to have a lot of painstaking work ahead of them in order to identify exactly how R5-/- individuals' usual HIV resistance sometimes breaks down.

Meanwhile, the arms race will continue. Viruses such as BDV, SARS and avian influenza will evolve ways to target new species. Hosts will evolve novel defense mechanisms that will in turn be breached by mutated viruses. However, understanding the underlying processes gives us a slight advantage that we can potentially leverage in the form of new anti-viral drugs and targeted treatments for people with different genetic profiles. We may never win the war, but tactical advances might just win us a few battles.

Source: http://vwxynot.blogspot.com/2007/07/field-dis...