|Genetic Variability: Implications for the Development of HIV Vaccines (UNAIDS, 1996, 16 p.)|
The extensive genetic variability of HIV is primarily due to the high error rates of the viral reverse transcriptase, which results in approximately 10 genomic base changes per replication cycle. In addition to substitutions, deletions and insertions also occur, although the frequency of these genetic errors is more difficult to estimate. The envelope gene (env) seems to be subject to the most extensive genetic variation, although alterations also occur in other genes [7,8,11-13]. HIV-1 undergoes continuous genetic variability within individual patients, who usually harbour a swarm of highly related but individually distinguishable viral variants, which are referred to as quasispecies, with a heterogeneity usually not exceeding 2-5% in the env gene [19,20].
On the other hand, a broad range of viral genetic variability (in the range of 20-30% in the env gene) has been documented for isolates from distinct geographical locations. This phenomenon is largely attributable to differential geographic distribution of the multiple genetic subtypes of HIV-1. Within a single geographic region, the range of genetic variability in the env gene is estimated to be 6-19%, although differences higher than 30% have been documented [8-13,21,24]. The extent of genetic variability in a given geographical location increases over time after the introduction of a particular subtype in a population. Initially, the heterogeneity in the env gene can be as low as 3-5%, which is comparable with the range of intra-patient variability, with further diversification at an estimated rate of approximately 1% per year. If immune protection is dependent on variable HIV sequences, then HIV vaccine development will become a moving target, which may require the continuous adaptation of specific vaccines, as is the case today with influenza vaccines.
In addition, recent data have provided evidence that genomic recombination between two different HIV-1 populations frequently occurs in vivo, resulting in biologically viable viruses with mosaic genomes, a phenomenon which may result in additional HIV genetic variability and viral genetic shifts [25-28]. The identification of these recombinant viruses indicates that co-infection, or super-infection, with different genetic variants of HIV-1 does happen in nature, and this may suggest that active infection with one virus strain does not necessarily confer complete protection against infection with another strain. However, experiments with live-attenuated SIV vaccines in macaques suggest that protection against super-infection is achieved only after an extended period during which protective mechanisms, involving either immune responses or target cell resistance due to interference, are developed in response to the initial virus infection, and have reached the level required for protection.