Re: Finding wood among the trees 25 September 2003
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Brian T Foley,
HIV Researcher
Los Alamos National Lab, Los Alamos, NM USA 87545

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Re: Re: Finding wood among the trees

The Perth Group wrote:
“we will leave it to others to pursue further investigations of the nucleotide sequences in the databases and the phylogenetic trees of these viruses. In searching and investigating databases and phylogenetic trees we should be cognisant of what Sir John Maddox, the former editor of Nature wrote: "Is there a danger, in molecular biology, that the accumulation of data will get so far ahead of its assimilation into a conceptual framework that the data will eventually prove an encumbrance? Part of the trouble is that excitement of the chase leaves little time for reflection. And there are grants for producing data, but hardly any for standing back in contemplation". (1) “

I find this choice of a quote extremely ironic in this conversation. Sir John Maddox was referring precisely to the need for phylogenetic and other types of analyses of DNA, RNA and protein sequence data. Analyses of the sequences are needed in order to make sense of how they fit into the larger picture. Examining just two virus sequences and noting that they differ at 10% or 50% of their sites is rather meaningless until we look at the overall pattern of evolution of these and other viruses. Producing accurate phylogenetic trees is just one of many ways to visualize these patterns.

The Perth Group wrote:
“According to Esteban Domingo, one of the first researchers to search for variability in the genome of RNA viruses and to apply Eigen’s quasispecies concept to the genome of RNA viruses: “RNA viruses replicate near the error threshold for maintenance of genetic information, and an increase in mutation frequency during replication may drive RNA viruses to extinction in a process termed lethal mutagenesis.” Or “virus entry into error catastrophe”. Because of this he advocates the use of mutogenetic agents as anti-viral. (6,7) “

While it is true that RNA viruses mutate rapidly, the exact “threshold for maintenance of genetic information” is not the same for all viruses. It depends on recombination efficiency, population sizes within an individual host, transmission rate from host to host, and hundreds of other factors. This is why it is critically important to study as amny of these factors as possible in any attempt to understand an epidemic. As just one example, comparing global variablitily of HIV-1 M group viruses in a given year to Human Influenza Virus Type A(H1N1) or Human Influenza Virus Type A(H3N2) in the same year is useful only if one also compares the populations sizes and mechanisms of epidemic spread of the viruses. Most people have the type of contact that can result in influenza virus transmission (shaking hands, being near someone who coughs or sneezes, etc.) with far more people than they have sexual contact with or share needles with.

The hypothesis of driving an entire virus quasispecies to extinction through an increase in the mutation rate, is interesting. As far as I know, it has not been proven to be possible for any RNA virus yet. The process will be even more difficult for retroviruses which have an integrated DNA provirus stage in their life cycle, than for RNA viruses which have no proviral stage. One of the functions of the lentiviral Vif protein has been worked out in recent years, as reviewed this August by Goff:
Goff SP Death by deamination: a novel host restriction system for HIV-1. Cell. 2003 Aug 8;114(3):281-3. Review. PMID: 12914693

This funtion is to protect the virus from a mammalian cellular defense that involves hypermutation through deamination of DNA:RNA heteroduplexes. The existence of this deamination pathway does indeed suggest that it can protect mammals from productive infection with at least some classes of retroviruses. However, it is not clear that this type of strategy can work for therapy after a long-standing infection, as well as it might work in preventing the initial spike of viremia imediately following infection. Vif protein inhibitors may work better as “vaccines” than as “therapy”.

Competing interests:   None declared