The origins of acquired immune deficiency syndrome viruses: where and when?

In the absence of direct epidemiological evidence, molecular evolutionary studies of primate lentiviruses provide the most definitive information about the origins of human immunodeficiency virus (HIV)-1 and HIV-2. Related lentiviruses have been found infecting numerous species of primates in sub-Saharan Africa. The only species naturally infected with viruses closely related to HIV-2 is the sooty mangabey (Cercocebus atys) from western Africa, the region where HIV-2 is known to be endemic. Similarly, the only viruses very closely related to HIV-1 have been isolated from chimpanzees (Pan troglodytes), and in particular those from western equatorial Africa, again coinciding with the region that appears to be the hearth of the HIV-1 pandemic. HIV-1 and HIV-2 have each arisen several times: in the case of HIV-1, the three groups (M, N and O) are the result of independent cross-species transmission events. Consistent with the phylogenetic position of a 'fossil' virus from 1959, molecular clock analyses using realistic models of HIV-1 sequence evolution place the last common ancestor of the M group prior to 1940, and several lines of evidence indicate that the jump from chimpanzees to humans occurred before then. Both the inferred geographical origin of HIV-1 and the timing of the cross-species transmission are inconsistent with the suggestion that oral polio vaccines, putatively contaminated with viruses from chimpanzees in eastern equatorial Africa in the late 1950s, could be responsible for the origin of acquired immune deficiency syndrome.

Origins and evolution of AIDS viruses: estimating the time-scale.

The primate lentiviruses comprise SIV strains from various host species, as well as two viruses, HIV-1 and HIV-2, that cause AIDS in humans. The origins of HIV-1 and HIV-2 have been traced to cross-species transmissions from chimpanzees and sooty mangabey monkeys respectively. Two approaches have been taken to estimate the time-scale of the evolution of these viruses. Certain groups of SIV strains appear to have evolved in a host-dependent manner, implying a time-scale of many thousands or even millions of years. In stark contrast, molecular clock calculations have previously been used to estimate a time-scale of only tens or hundreds of years. Those calculations largely ignored heterogeneity of evolutionary rates across different sites within sequences. In fact, the distribution of rates at different sites seems extremely skewed in HIV-1, and so the time-depth of the primate lentivirus evolutionary tree may have been underestimated by at least a factor of ten. However, these date estimates still seem to be far too recent to be consistent with host-dependent evolution.

Patterns of genomic sequence diversity among their simian immunodeficiency viruses suggest that L'Hoest monkeys (Cercopithecus lhoesti) are a natural lentivirus reservoir.

Recently, we described a novel simian immunodeficiency virus (SIVlhoest) from a wild-caught L'Hoest monkey (Cercopithecus lhoesti) from a North American zoo. To investigate whether L'Hoest monkeys are the natural host for these viruses, we have screened blood samples from 14 wild animals from the Democratic Republic of Congo. Eight (57%) were found to be seropositive for SIV. Nearly full-length genome sequences were obtained for SIV isolates from three of these monkeys and compared to the original isolate and to other SIVs. The four samples of SIVlhoest formed a distinct cluster in phylogenetic trees. Two of these isolates differed on average at only about 5% of nucleotides, suggesting that they were epidemiologically linked; otherwise, the SIVlhoest isolates differed on average by 18%. Both the level of diversity and the pattern of its variation along the genome were very similar to those seen among isolates of SIVagm from vervet monkeys, pointing to similarities in the nature of, and constraints on, SIV evolution in these two species. Discordant phylogenetic relationships among the SIVlhoest isolates for different genomic regions indicated that mosaic viruses have been generated by recombination, implying that individual monkeys have been coinfected by more than one strain of SIV. Taken together, these observations provide strong evidence that L'Hoest monkeys constitute a natural reservoir for SIV.

Simian immunodeficiency virus (SIV) from sun-tailed monkeys (Cercopithecus solatus): evidence for host-dependent evolution of SIV within the C. lhoesti superspecies.

Recently we reported the characterization of simian immunodeficiency virus (SIVlhoest) from a central African l'hoest monkey (Cercopithecus lhoesti lhoesti) that revealed a distant relationship to SIV isolated from a mandrill (SIVmnd). The present report describes a novel SIV (SIVsun) isolated from a healthy, wild-caught sun-tailed monkey (Cercopithecus lhoesti solatus), another member of the l'hoest superspecies. SIVsun replicated in a variety of human T-cell lines and in peripheral blood mononuclear cells of macaques (Macaca spp.) and patas monkeys (Erythrocebus patas). A full-length infectious clone of SIVsun was derived, and genetic analysis revealed that SIVsun was most closely related to SIVlhoest, with an amino acid identity of 71% in Gag, 73% in Pol, and 67% in Env. This degree of similarity is reminiscent of that observed between SIVagm isolates from vervet, grivet, and tantalus species of African green monkeys. The close relationship between SIVsun and SIVlhoest, despite their geographically distinct habitats, is consistent with evolution from a common ancestor, providing further evidence for the ancient nature of the primate lentivirus family. In addition, this observation leads us to suggest that the SIVmnd lineage should be designated the SIVlhoest lineage.

Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes.

The human AIDS viruses human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) represent cross-species (zoonotic) infections. Although the primate reservoir of HIV-2 has been clearly identified as the sooty mangabey (Cercocebus atys), the origin of HIV-1 remains uncertain. Viruses related to HIV-1 have been isolated from the common chimpanzee (Pan troglodytes), but only three such SIVcpz infections have been documented, one of which involved a virus so divergent that it might represent a different primate lentiviral lineage. In a search for the HIV-1 reservoir, we have now sequenced the genome of a new SIVcpzstrain (SIVcpzUS) and have determined, by mitochondrial DNA analysis, the subspecies identity of all known SIVcpz-infected chimpanzees. We find that two chimpanzee subspecies in Africa, the central P. t. troglodytes and the eastern P. t. schweinfurthii, harbour SIVcpz and that their respective viruses form two highly divergent (but subspecies-specific) phylogenetic lineages. All HIV-1 strains known to infect man, including HIV-1 groups M, N and O, are closely related to just one of these SIVcpz lineages, that found in P. t. troglodytes. Moreover, we find that HIV-1 group N is a mosaic of SIVcpzUS- and HIV-1-related sequences, indicating an ancestral recombination event in a chimpanzee host. These results, together with the observation that the natural range of P. t. troglodytes coincides uniquely with areas of HIV-1 group M, N and O endemicity, indicate that P. t. troglodytes is the primary reservoir for HIV-1 and has been the source of at least three independent introductions of SIVcpz into the human population.

Characterization of a novel simian immunodeficiency virus (SIV) from L'Hoest monkeys (Cercopithecus l'hoesti): implications for the origins of SIVmnd and other primate lentiviruses.

The human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) appear to have originated by cross-species transmission of simian immunodeficiency virus (SIV) from asymptomatically infected African primates. Few of the SIVs characterized to date efficiently infect human primary lymphocytes. Interesting, two of the three identified to infect such cultures (SIVsm and SIVcpz) have appeared in human populations as genetically related HIVs. In the present study, we characterized a novel SIV isolate from an East African monkey of the Cercopithecus genus, the l'hoest monkey (C. l'hoesti), which we designated SIVlhoest. This SIV isolate efficiently infected both human and macaque lymphocytes and resulted in a persistent infection of macaques, characterized by high primary virus load and a progressive decline in circulating CD4 lymphocytes, consistent with progression to AIDS. Phylogenetic analyses showed that SIVlhoest is genetically distinct from other previously characterized primate lentiviruses but clusters in the same major lineage as SIV from mandrills (SIVmnd), a West African primate species. Given the geographic distance between the ranges of l'hoest monkeys and mandrills, this may indicate that SIVmnd arose through cross-species transmission from close relatives of l'hoest monkeys that are sympatric with mandrills. These observations lend support to the hypothesis that the primate lentiviruses originated and coevolved within monkeys of the Cercopithecus genus. Regarded in this light, lentivirus infections of primates not belonging to the Cercopithecus genus may have resulted from cross-species transmission in the not-too-distant past.

An isolate of human immunodeficiency virus type 1 originally classified as subtype I represents a complex mosaic comprising three different group M subtypes (A, G, and I).

Full-length reference clones and sequences are currently available for eight human immunodeficiency virus type 1 (HIV-1) group M subtypes (A through H), but none have been reported for subtypes I and J, which have only been identified in a few individuals. Phylogenetic information for subtype I, in particular, is limited since only about 400 bp of env gene sequences have been determined for just two epidemiologically linked viruses infecting a couple who were heterosexual intravenous drug users from Cyprus. To characterize subtype I in greater detail, we employed long-range PCR to clone a full-length provirus (94CY032.3) from an isolate obtained from one of the individuals originally reported to be infected with this subtype. Phylogenetic analysis of C2-V3 env gene sequences confirmed that 94CY032.3 was closely related to sequences previously classified as subtype I. However, analysis of the remainder of its genome revealed various regions in which 94CY032.3 was significantly clustered with either subtype A or subtype G. Only sequences located in vpr and nef, as well as the middle portions of pol and env, formed independent lineages roughly equidistant from all other known subtypes. Since these latter regions most likely have a common origin, we classify them all as subtype I. These results thus indicate that the originally reported prototypic subtype I isolate 94CY032 represents a triple recombinant (A/G/I) with at least 11 points of recombination crossover. We also screened HIV-1 recombinants with regions of uncertain subtype assignment for the presence of subtype I sequences. This analysis revealed that two of the earliest mosaics from Africa, Z321B (A/G/?) and MAL (A/D/?), contain short segments of sequence which clustered closely with the subtype I domains of 94CY032.3. Since Z321 was isolated in 1976, subtype I as well as subtypes A and G must have existed in Central Africa prior to that date. The discovery of subtype I in HIV-1 hybrids from widely distant geographic locations also suggests a more widespread distribution of this virus subtype, or at least segments of it, than previously recognized.