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Research Article

Impact of HIV-1 Subtype and Antiretroviral Therapy on Protease and Reverse Transcriptase Genotype: Results of a Global Collaboration

  • Rami Kantor mail,

    *To whom correspondence should be addressed. E-mail: rkantor@ brown.edu

    Affiliation: Division of Infectious Disease and Center for AIDS Research, Stanford University, Stanford, California, United States of America

    ¤Current affiliation: Division of Infectious Diseases, Brown University, Providence, Rhode Island, United States of America

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  • David A Katzenstein,

    Affiliation: Division of Infectious Disease and Center for AIDS Research, Stanford University, Stanford, California, United States of America

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  • Brad Efron,

    Affiliation: Department of Statistics and Division of Biostatistics, Stanford University, Stanford, California, United States of America

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  • Ana Patricia Carvalho,

    Affiliation: Hospital Egas Moniz, Lisbon, Portugal

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  • Brian Wynhoven,

    Affiliation: BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada

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  • Patricia Cane,

    Affiliation: Health Protection Agency, Porton Down, United Kingdom

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  • John Clarke,

    Affiliation: Wright Fleming Institute, Imperial College, St. Mary's Hospital, London, United Kingdom

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  • Sunee Sirivichayakul,

    Affiliation: Chulalongkorn University, Bangkok, Thailand

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  • Marcelo A Soares,

    Affiliation: Universidade Federal do Rio de Janeiro, Brazil

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  • Joke Snoeck,

    Affiliation: Rega Institute for Medical Research, Leuven, Belgium

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  • Candice Pillay,

    Affiliation: National Institute of Communicable Diseases, Johannesburg, South Africa

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  • Hagit Rudich,

    Affiliation: Central Virology, Public Health Laboratories, Ministry of Health, Tel-Hashomer, Israel

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  • Rosangela Rodrigues,

    Affiliation: Instituto Adolfo Lutz, Sao Paulo, Brazil

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  • Africa Holguin,

    Affiliation: Hospital Carlos III, Madrid, Spain

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  • Koya Ariyoshi,

    Affiliation: National Institute of Infectious Diseases, Tokyo, Japan

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  • Maria Belen Bouzas,

    Affiliation: Fundación Huesped, Buenos Aires, Argentina

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  • Pedro Cahn,

    Affiliation: Fundación Huesped, Buenos Aires, Argentina

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  • Wataru Sugiura,

    Affiliation: National Institute of Infectious Diseases, Tokyo, Japan

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  • Vincent Soriano,

    Affiliation: Hospital Carlos III, Madrid, Spain

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  • Luis F Brigido,

    Affiliation: Instituto Adolfo Lutz, Sao Paulo, Brazil

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  • Zehava Grossman,

    Affiliation: Central Virology, Public Health Laboratories, Ministry of Health, Tel-Hashomer, Israel

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  • Lynn Morris,

    Affiliation: National Institute of Communicable Diseases, Johannesburg, South Africa

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  • Anne-Mieke Vandamme,

    Affiliation: Rega Institute for Medical Research, Leuven, Belgium

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  • Amilcar Tanuri,

    Affiliation: Universidade Federal do Rio de Janeiro, Brazil

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  • Praphan Phanuphak,

    Affiliation: Chulalongkorn University, Bangkok, Thailand

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  • Jonathan N Weber,

    Affiliation: Wright Fleming Institute, Imperial College, St. Mary's Hospital, London, United Kingdom

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  • Deenan Pillay,

    Affiliation: University College London and Health Protection Agency, London, United Kingdom

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  • P. Richard Harrigan,

    Affiliation: BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada

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  • Ricardo Camacho,

    Affiliation: Hospital Egas Moniz, Lisbon, Portugal

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  • Jonathan M Schapiro,

    Affiliation: Division of Infectious Disease and Center for AIDS Research, Stanford University, Stanford, California, United States of America

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  • Robert W Shafer

    Affiliation: Division of Infectious Disease and Center for AIDS Research, Stanford University, Stanford, California, United States of America

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  • Published: April 26, 2005
  • DOI: 10.1371/journal.pmed.0020112

Reader Comments (2)

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Authors' Reply

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 [6] and distinct lineages within the same subtype have also been described [7]. Moreover, in several cases these lineages have been characterized by specific, but fortunately, rather minor drug-resistance mutations (e.g. A62V in RT [8] and V77I in protease [9]). 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.

References

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2. Korber B, Muldoon M, Theiler J, Gao F, Gupta R et al. (2000) Timing the ancestor of the HIV-1 pandemic strains. Science 288: 1789-1796.
3. Salemi M, Strimmer K, Hall WW, Duffy M, Delaporte E, et al. (2001) Dating the common ancestor of SIVcpz and HIV-1 group M and the origin of HIV-1 subtypes using a new method to uncover clock-like molecular evolution. FASEB J 15(2):276-8.
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7. Hue S, Pillay D, Clewley JP, Pybus OG (2005) Genetic analysis reveals the complex structure of HIV-1 transmission within defined risk groups. Proc Natl Acad Sci U S A 102(12): 4425-4429.
8. Carr JK, Nadai Y, Eyzaguirre L, Saad MD, Khakimov MM et al. (2005) Outbreak of a West African recombinant of HIV-1 in Tashkent, Uzbekistan. J Acquir Immune Defic Syndr 39(5): 570-575.
9. Roudinskii NI, Sukhanova AL, Kazennova EV, Weber JN, Pokrovsky VV et al. (2004) Diversity of human immunodeficiency virus type 1 subtype A and CRF03_AB protease in Eastern Europe: selection of the V77I variant and its rapid spread in injecting drug user populations. J Virol 78(20): 11276-11287.

No competing interests declared.