Variation in HIV: Evolution or Noise?

Such a question has been posed for the variation observed in RNA viruses in general;[30] for HIV, the answer is probably a lot of each. HIV generates variants at a far greater rate than do other RNA viruses such as measles, polio and even influenza[31] (Fig. 2). The rapid radiation of HIV-1 group M into the subtypes or clades that comprise today's pandemic strains and all of their variants could have arisen from a conjunction of two features of HIV: the extraordinarily high level of sustained replication and turnover in vivo[11,32] and the functional tolerance of amino acid substitutions.

(Enlarge Image) The scale of HIV variation. Sequence divergence of envelope glycoproteins of HIV (gp120, V2-C5) compared with that of influenza A H3 (HA1). The length of the spokes indicates the degree of divergence with the scale indicated. HIV variation in a single person 6 years after infection (9 genomes analyzed) is similar to that of worldwide influenza A (96 genomes analyzed) in a single year. The greatest degree of variation is in the Democratic Republic of Congo, where HIV first developed and has diversified into subtypes A-K (except for subtype B, prevalent in the West, and subtype E, prevalent in Thailand). Adapted with permission from ref. 31.

It is estimated that humans were first infected with HIV-1 group M about 70 years ago[33] and with HIV-2 about 60 years ago,[34] with the viruses crossing from chimpanzees and sooty mangabeys, respectively.[35] In the early years, HIV-1 radiated out into the different clades that we know today, probably from small founder populations of virus. The regions in which HIV-1 has been present the longest have the most complex array of genotypes (Fig. 2). In the next 20 years the pattern will change, and an increasing number of circulating recombinant forms (CRFs) of HIV-1 will become apparent. Thus, the neat geographic delineation of subtypesB in the Americas, E in Thailand, A and D in East Africa and C in southern Africaare likely to be superseded by CRF viruses. Indeed, CRFs between HIV-1 groups M and O have been described,[36] even though the parental genomes derive from distinct zoonotic events.[35] It is possible that natural recombinants could arise between HIV-1 and HIV-2 now that HIV-1 has spread across West Africa, where HIV-2 was already endemic. Although there are some constraints to the co-packaging of HIV-1 and HIV-2 RNA37, it is worth investigating the possibility of hybrids in dually infected persons.

Does HIV variation matter? Although there is no evidence that HIV has evolved in terms of virulence or modes of transmission in the past 20 years, evolution of drug resistance[12] and of immune escape (see accompanying review in this issue[38,39,40] and clearly occurs under selective pressure. Thus, HIV mutation and recombination have a great impact on therapy and vaccine design. I remain to be convinced, however, that the emphasis of vaccine design on the basis of clades is HIV science. Efficacious, broadly based vaccines require immunogens representing those regions of the virus that change the least. When these have been identified, clades can be addressed. For humoral immunity, the challenge is not only the immunogen itself but also the access of antibodies to the neutralization targets. Given the effect of the N-linked sugars of gp120 on immune escape from HIV,[39] the glycobiology of HIV is back in fashion.

Will the drop in AIDS mortality owing to antiretroviral therapy (Fig. 1) be maintained so that people on treatment can expect a normal life span? This will depend on the ability of the virus to develop multidrug resistance while remaining fit for transmission. We shall need new drug targets,[12] but a big practical challenge in the future will be to marry good drug therapy to easy adherence, particularly in resource-poor settings. This means that drug formulation must be designed to optimize appropriate use. Even then, if drugs administered to one infected individual are shared among their family or community such that several persons are simultaneously taking suboptimal doses, this could be a recipe for the rapid evolution and spread of multidrug-resistant HIV strains.

In the future, I expect that host genetic variation will also have a larger role in HIV science. In addition to identifying individual host factors,[26,41,42,43] whole-genome scanning for pharmacogenomics and for what I call 'infectogenomics' (host genes that affect the virulence of infection) will provide information on how to better manage HIV infection.