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Response to ‘On HIV-1 genetic diversity in Cuba’ by Ruibal et al.

Thomson, Michael M; Delgado, Elena; Medrano, Leandro; Pérez-Alvarez, Lucía; Contreras, Gerardo; Nájera, Rafael

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The assertion by Ruibal et al. that the paper ‘High HIV-1 genetic diversity in Cuba’ [1] was published without approval of the Cuban co-authors is surprising to us. The original and corrected manuscripts were sent to our Cuban colleagues before their submission to AIDS. Moreover, they suggested a few modifications, all of which were incorporated in the final version mailed to AIDS. All authors were informed of the acceptance for publication. After receiving the proofs, we e-mailed our Cuban colleagues in case they would consider any final corrections. There was no reply to this message. The authors’ acceptance form was also faxed to them, with the request that they sign it and send it to the AIDS editorial office. As there was no further communication from the AIDS editorial office, we assumed that all signatures had been received.

Ruibal et al. say that non-subtype B viruses, as identified by env heteroduplex mobility assay (HMA), and cases diagnosed more than 3 years earlier, with high-risk sexual behaviour, a lack of therapeutic adherence, or therapeutic failure were deliberately included in the study. This information, previously unknown to us, was not mentioned by our Cuban colleagues among their corrections to the manuscript. Regarding the time of diagnosis, 56% were diagnosed less than 3 years before sample collection in 1999, of which 46% were non-B subtypes, not significantly different from 52% for all samples. Regarding therapeutic failures, only 11 subjects (10%) could be described as such (viral loads > 500 copies/ml under triple antiretroviral drug therapy); of these, five were non-B subtypes. With respect to risk categories, the distribution was very similar to that of the whole HIV-1-infected population in Cuba [2]. As to the deliberate excess inclusion by our Cuban colleagues of non-B samples, it is difficult to reconcile that with the fact that, according to data provided by them, of 97 samples previously characterized by env HMA, 74 (76.3%) were identified by this method as B subtypes (a substantial proportion of which turned out to be non-B or recombinant in our pol/env sequence analysis). This is similar to the 70% (also by env HMA) found in their study described by them as ‘representative of the HIV-1 population in Cuba’ (published in a Cuban journal unavailable to us) [3], which argues against an overrepresentation of non-B subtypes in our study. This is also in disagreement with another study, mentioned by Ruibal et al., in which recent (2000–2001) HIV-1 diagnoses in Havana were analysed by env and gag HMA. According to the abstract of the poster [4], the proportion of subtype B was only 33.5% in gag and 35% in env, which would be higher, in agreement with our paper, only relative to each of the other subtypes or recombinants considered individually. Therefore, we think that discrepancies between our sequencing and the Cuban HMA studies are mostly of methodological origin, related to the relatively low accuracy of HMA [5,6], and possibly to other factors such as intersample polymerase chain reaction contamination (detectable by phylogenetic sequence analysis but not by HMA), rather than to sampling biases. This is supported by the comparison of HMA and sequencing results of the samples from our study: among 95 samples analysed by both methods, 34 (35.8%) had discordant results. Among non-B subtypes, 25 (59.5%) out of 42 were incorrectly classified as subtype B by HMA. The reverse error, identifying a subtype B virus as non-B, occurred in six out of 53 cases (11.3%). In addition, in our study, four samples with env B sequences were non-B or recombinant in pol.

Nowhere in our paper was it said that ‘the apparition of new circulating recombinant forms constitute a threat to other countries’ as Ruibal et al. assert. What was said was that the possibility of exporting some of the genetic forms from Cuba to other countries ‘may not be negligible'. In fact, we have identified one HIV-1 BG recombinant of Cuban origin in Spain (unpublished data). The assertion was made in the context of an increase in prostitution related to the expansion of tourism in recent years [7–9], and of a recently reported sharp increase in HIV-1 infections in Cuba [10]. The risk for tourists should not be exaggerated, because Cuba, as mentioned in our paper, reportedly has among the lowest HIV prevalences in the Americas, according to UNAIDS estimations [2]. However, as the rapid propagation of HIV genetic forms may occur within promiscuous sexual networks, the recommendation of using condoms in casual sexual contacts applies for tourists visiting Cuba as well as in any other country. Regarding the African origin of the Cuban recombinants, this is not deduced from epidemiological data, but from phylogenetic sequence analysis: Cuban U/H and D/A recombinants, which form well-supported clusters in phylogenetic trees, group with high bootstrap values with isolates reported outside Cuba, only in west-central or west Africa. The putative parentals were not found in Cuba, which suggests that the recombinants circulating in Cuba originated in Africa. It is also important to note that among HIV-1 infections diagnosed in Cuba up to 1990, 25% were directly traceable to Africa [11].

Finally, for a complete study on HIV-1 genetic diversity in Cuba, considering the frequent detection of unique recombinants, it would be necessary to analyse the full-length genome sequences of a representative sample, a feasible study, given the low number of HIV-1 infections in Cuba.

References

1. Cuevas MT, Ruibal I, Villahermosa ML, Díaz HM, Delgado E, Vázquez de Parga E, et al. High HIV-1 genetic diversity in Cuba.AIDS 2002, 16:1643–1653.
2. UNAIDS. Global HIV/AI/AIDS and STD surveillance. Epidemiological fact sheets by country. 2002 update. http://www.unaids. org.
3. Blanco M, Rolo F, Martínez N, Gessa A, Díaz HM, Lubián AL. Application of heteroduplex mobility assay in molecular epidemiology study of HIV-1 in Cuba.Biotecnología Aplicada 2001, 18:149–153.
4. Blanco M, Martínez M, Díaz HM, Lubián AL, Romay D, Regalado L, et al. Application ofgag/envHMA in the molecular epidemiology study of the HIV-1 in Cuba. In: XIVth International AIDS Conference. Barcelona, 7–12 July 2002 [Abstract TuPeC 4796].
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© 2003 Lippincott Williams & Wilkins, Inc.