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Posted by plosmedicine on 31 Mar 2009 at 00:02 GMT
Author: Rami Kantor
Position: Division of Infectious Diseases
Institution: Brown University, Providence, Rhode Island, USA
E-mail: rkantor@ brown.edu
Additional Authors: David A. Katzenstein, Ricardo J. Camacho, Ana B. Abecasis, Anne-Mieke Vandamme, Robert W, Shafer for the HIV-1 Non-Subtype B Working Group
Submitted Date: December 01, 2006
Published Date: December 4, 2006
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.
The HIV-1 pandemic resulted from the cross-species transmission of a primate lentivirus from a chimpanzee in western sub-Saharan Africa and its subsequent spread within humans beginning in the first half of the previous century [1,2,3]. As this virus spread among humans, it has developed a bewildering amount of genetic diversity through a process of mutation, founder effect, and recombination giving rise to a complex system of subtypes, well-characterized circulating recombinant forms (CRFs), and non-CRF recombinants. Beginning in 2000, leading researchers in the field have established a useful nomenclature, which has been continually updated through the Los Alamos HIV Sequence Database [4,5].
Ojesina and Kanki, however, correctly point out that despite the complexity of subtyping system, it still does not completely account for the genetic diversity of worldwide HIV-1 variants. For example, several sub-subtypes have been reported  and distinct lineages within the same subtype have also been described . Moreover, in several cases these lineages have been characterized by specific, but fortunately, rather minor drug-resistance mutations (e.g. A62V in RT  and V77I in protease ). A98S is not a drug-resistance mutation - a different mutation at the same position, A98G, causes 2-fold decreases in susceptibility to each of the nonnucleoside RT inhibitors. Nonetheless, as Ojesina and Kanki claim, the different prevalence of the A98S variant in subtype G viruses from Nigeria as compared with Spain and Portugal almost certainly results from a founder effect. We further investigated this founder effect by analyzing the phylogenetic branch along which A98S arose within subtype G using strains from around the world and including the Portuguese-Spanish epidemic (manuscript in preparation). As Ojesina and Kanki suggested, there is indeed a founder effect in the Iberian peninsula with the majority of subtype G strains from that area clustering together, and some other isolated introductions of subtype G. However, our analysis clearly shows that although A98S was introduced in the main Iberian subtype G clade, as a result of this founder effect, it was also introduced a second time in a clade originating from Cameroon-Senegal, and it was indeed not found in subtype G from Nigeria.
These results, the letter by Ojesina and Kanki and the discussion in our manuscript argue that population stratification complicates statistical comparisons of the prevalence of HIV-1 mutations between different subtypes. Therefore, we agree with Ojesina and Kanki that some of the polymorphic differences we observed between subtypes may have been biased by population stratification, whereas other polymorphic differences between subtypes may eventually be confirmed in multiple different populations in different geographic regions. Differential mapping of such polymorphisms will only be possible through the ongoing collection of global HIV-1 sequence data and its submission to public databases, and will also require new tools taking into account molecular epidemiological information into statistical methods.
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