GENETIC DIVERSITY OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-2 - EVIDENCE FOR DISTINCT SEQUENCE SUBTYPES WITH DIFFERENCES IN VIRUS BIOLOGY

The virulence properties of human immunodeficiency virus type 2 (HIV-2 ) are known to vary significantly and to range from relative attenuati on in certain individuals to high level pathogenicity in others. These differences in clinical manifestations may, at least in part, be dete rmined by genetic differences among infecting virus strains. Evaluatio n of the full spectrum of HIV-2 genetic diversity is thus a necessary first step towards understanding its molecular epidemiology, natural h istory of infection, and biological diversity. In this study, we have used nested PCR techniques to amplify viral sequences from the DNA of uncultured peripheral blood mononuclear cells from 12 patients with HI V-2 seroreactivity. Sequence analysis of four nonoverlapping genomic r egions allowed a comprehensive analysis of HIV-2 phylogeny. The result s revealed (i) the existence of five distinct and roughly equidistant evolutionary lineages of HIV-2 which, by analogy with HIV-1, have been termed sequence subtypes A to E; (ii) evidence for a mosaic HIV-2 gen ome, indicating that coinfection with genetically divergent strains an d recombination can occur in HIV-2-infected individuals; and (iii) evi dence supporting the conclusion that some of the HIV-2 subtypes may ha ve arisen from independent introductions of genetically diverse sooty mangabey viruses into the human population. Importantly, only a subset of HIV-2 strains replicated in culture: all subtype A viruses grew to high titers, but attempts to isolate representatives of subtypes C, D , and E, as well as the majority of subtype B viruses, remained unsucc essful. Infection with all five viral subtypes was detectable by comme rcially available serological (Western immunoblot) assays, despite int ersubtype sequence differences of up to 25% in the gag, pol, and env r egions. These results indicate that the genetic and biological diversi ty of HIV-2 is far greater than previously appreciated and suggest tha t there may be subtype-specific differences in virus biology. Systemat ic natural history studies are needed to determine whether this hetero geneity has clinical relevance and whether the various HIV-2 subtypes differ in their in vivo pathogenicity.