Development of a vaccine that may significantly slow down the global HIV-1 epidemic is hindered, in large part, by the extensive genetic heterogeneity of the virus caused by lack of proofreading activity of the reverse transcriptase, coupled with high replication and recombination rate. Any effective large-scale immunization strategy will depend on the availability of robust molecular epidemiology data on HIV-1 subtype distribution. The work of Hemelaar et al., which analyzed an impressive dataset of 65 913 samples from HIV-1-infected patients in 109 countries during 2000–2007, is a significant step forward in this direction.
The distribution of HIV-1 subtypes is usually inferred from meta-analysis of existing literature, an approach often hampered by publication bias and lack of standardization , as Hemelaar et al. rightly note. In contrast, the authors of the new study combined a thorough survey of the literature with subtype statistics from the WHO–UNAIDS Network for HIV Isolation and Characterisation. Moreover, their analysis took into account UNAIDS/WHO estimates of the average number of HIV-1 infections by country during 2000–2003 and 2004–2007 [3,4]. The result is a detailed series of maps (available in full in the supplemental data files of the paper) showing the worldwide prevalence of the nine HIV-1 subtypes, the three major circulating recombinant forms (CRF01_AE, CRF01_AG and CRF01_AB), as well as other CRFs and unique recombinant forms (URFs).
The Hemelaar et al. survey confirmed that HIV-1 is not a uniform pandemic but is characterized by a strong spatial structure more accurately described as a collection of regional epidemics with specific subtype distributions and dynamics. In agreement with previous reports, the authors found that subtype C is the most prevalent worldwide, accounting for almost half of the infections, followed by subtypes A and B and CFR02-AG.
Interestingly, the comparison of 2004–2007 data with the ones from the preceding 4 years showed that although global subtype distribution remained very similar overall, the number of infections caused by CRFs increased by at least 50%. In particular, CRF02_AG infections jumped from 5 to 8%, representing 900 000 additional cases. However, because subtyping is all too often based only on partial genome sequences, a systematic generation of full-genome data, which could be enhanced by pyrosequencing techniques in the near future, will be necessary to assess the actual spread of CRFs. In addition, the authors caution that their results are based on cross-sectional studies and estimates of people living with the virus, rather than new infections. Therefore, the observed trends may substantially predate the time interval under investigation. Such concerns highlight the urgent need to investigate subtype incidence in different geographic areas.
The recent clinical trials of ALVAC and AIDSVAX have renewed hope in the possibility to develop an actual HIV-1 vaccine [5,6], although it is still controversial whether a single vaccine protecting against the major subtypes and CRFs is in fact possible. It seems more plausible that region-specific vaccines will be required to protect populations infected by viral strains circulating in discrete geographic areas. The data of Hemelaar et al. underline the dynamic nature of the HIV-1 epidemic. If a successful vaccine against one or more subtype will be developed, the population immunized against the dominant subtypes may become a niche of susceptible hosts among which emergent CRFs or URFs, fostered by positive selection, could rapidly spread giving rise to entirely new epidemic waves.
Apart from the impact on vaccination strategies, building research programs to monitor subtype incidence and prevalence can provide important clues to the longstanding, and only partially answered, questions about whether specific subtypes are associated with different transmission rates and/or disease progression [7–9]. Moreover, even in the era of HAART, the occurrence of AIDS-related neurological disorders seems to be increasing in infected patients [10,11], and it is still unclear how different HIV-1 subtypes affect the development of HIV-associated dementia (HAD) . A robust and continuous monitoring of viral subtypes and HAD prevalence and incidence in different countries is essential for providing the necessary knowledge base to address this issue.
The molecular epidemiology of HIV-1 subtypes could also shed light on the evolutionary and population dynamics of the virus. The temporal and geographic origins of HIV-1 Group M have been well characterized [13–15] but the reasons for the uneven distribution of subtypes and prevalence rates remain unresolved. Recently, the use of phylogenetic and geographic information data has shown great potential in explaining the early spread of HIV-1 in east Africa . Such studies could benefit considerably from reliable data on country-specific subtype distributions.
As Hemelaar et al. poignantly remarked in their conclusion, an improved and continuous global monitoring of HIV-1 genetic diversity has to be a major focus of twenty-first century molecular epidemiology. This will only happen through adequate investment of funds for national surveys based on statistically sound criteria, conducted as part of a highly coordinated worldwide effort.
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