Population genomics of domestic and wild yeasts.

Since the completion of the genome sequence of Saccharomyces cerevisiae in 1996 (refs 1, 2), there has been a large increase in complete genome sequences, accompanied by great advances in our understanding of genome evolution. Although little is known about the natural and life histories of yeasts in the wild, there are an increasing number of studies looking at ecological and geographic distributions, population structure and sexual versus asexual reproduction. Less well understood at the whole genome level are the evolutionary processes acting within populations and species that lead to adaptation to different environments, phenotypic differences and reproductive isolation. Here we present one- to fourfold or more coverage of the genome sequences of over seventy isolates of the baker's yeast S. cerevisiae and its closest relative, Saccharomyces paradoxus. We examine variation in gene content, single nucleotide polymorphisms, nucleotide insertions and deletions, copy numbers and transposable elements. We find that phenotypic variation broadly correlates with global genome-wide phylogenetic relationships. S. paradoxus populations are well delineated along geographic boundaries, whereas the variation among worldwide S. cerevisiae isolates shows less differentiation and is comparable to a single S. paradoxus population. Rather than one or two domestication events leading to the extant baker's yeasts, the population structure of S. cerevisiae consists of a few well-defined, geographically isolated lineages and many different mosaics of these lineages, supporting the idea that human influence provided the opportunity for cross-breeding and production of new combinations of pre-existing variations.

The presence of a vpu gene and the lack of Nef-mediated downmodulation of T cell receptor-CD3 are not always linked in primate lentiviruses.

Nef is an accessory protein critical for the ability of human and simian immunodeficiency viruses (HIV and SIV) to replicate efficiently in their respective hosts. Previous analyses of members of 15 different primate lentivirus lineages revealed a link between Nef function and the presence of a vpu gene. In particular, Nef proteins of all vpu-containing viruses had lost their ability to downmodulate the T cell (TCR-CD3) receptor. Here we examined Nef proteins from eight additional SIV lineages, including SIVgor, SIVwrc, SIVolc, SIVgri, SIVdrl, SIVlho, SIVden, and SIVasc, from western lowland gorillas, western red colobus monkeys, olive colobus monkeys, grivet monkeys, drills, L'Hoest's monkeys, Dent's mona monkeys, and red-tailed monkeys, respectively. We found that except for the nef gene of SIVdrl, all of them were efficiently expressed and modulated CD4, major histocompatibility complex class I (MHC-I), CD28, CXCR4, and Ii cell surface expression and/or enhanced viral infectivity and replication. Furthermore, the Nef proteins of SIVgri, SIVlho, SIVwrc, SIVolc, and SIVgor antagonized tetherin. As expected, the Nef protein of SIVgor, which carries vpu, failed to downmodulate CD3, whereas those of SIVwrc, SIVgri, SIVlho, and SIVasc, which lack vpu, were capable of performing this function. Surprisingly, however, the Nef protein of the vpu-containing SIVden strain retained the ability to downmodulate TCR-CD3, whereas that of SIVolc, which does not contain vpu, was unable to perform this function. Although the SIVden Vpu is about 20 amino acids shorter than other Vpu proteins, it degrades CD4 and antagonizes tetherin. Our data show that there are exceptions to the link between the presence of a vpu gene and nef alleles deficient in CD3 modulation, indicating that host properties also affect the selective pressure for Nef-mediated disruption of TCR-CD3 signaling. Our results are also further evidence that tetherin antagonism is a common function of primate lentivirus Nef proteins and that the resistance of human tetherin to Nef represents a relevant barrier to cross-species transmission of SIVs to humans.

Human immunodeficiency viruses: SIV infection in wild gorillas.

Chimpanzees (Pan troglodytes troglodytes) from west central Africa are recognized as the reservoir of simian immunodeficiency viruses (SIVcpzPtt) that have crossed at least twice to humans: this resulted in the AIDS pandemic (from human immunodeficiency virus HIV-1 group M) in one instance and infection of just a few individuals in Cameroon (by HIV-1 group N) in another. A third HIV-1 lineage (group O) from west central Africa also falls within the SIVcpzPtt radiation, but the primate reservoir of this virus has not been identified. Here we report the discovery of HIV-1 group O-like viruses in wild gorillas.

Segregating YKU80 and TLC1 alleles underlying natural variation in telomere properties in wild yeast.

In yeast, as in humans, telomere length varies among individuals and is controlled by multiple loci. In a quest to define the extent of variation in telomere length, we screened 112 wild-type Saccharomyces sensu stricto isolates. We found extensive telomere length variation in S. paradoxus isolates. This phenotype correlated with their geographic origin: European strains were observed to have extremely short telomeres (<150 bp), whereas American isolates had telomeres approximately three times as long (>400 bp). Insertions of a URA3 gene near telomeres allowed accurate analysis of individual telomere lengths and telomere position effect (TPE). Crossing the American and European strains resulted in F1 spores with a continuum of telomere lengths consistent with what would be predicted if many quantitative trait loci (QTLs) were involved in length maintenance. Variation in TPE is similarly quantitative but only weakly correlated with telomere length. Genotyping F1 segregants indicated several QTLs associated with telomere length and silencing variation. These QTLs include likely candidate genes but also map to regions where there are no known genes involved in telomeric properties. We detected transgressive segregation for both phenotypes. We validated by reciprocal hemizygosity that YKU80 and TLC1 are telomere-length QTLs in the two S. paradoxus subpopulations. Furthermore, we propose that sequence divergence within the Ku heterodimer generates negative epistasis within one of the allelic combinations (American-YKU70 and European-YKU80) resulting in very short telomeres.

A limited number of simian immunodeficiency virus (SIV) env variants are transmitted to rhesus macaques vaginally inoculated with SIVmac251.

Single-genome amplification (SGA) and sequencing of HIV-1 RNA in plasma of acutely infected humans allows the identification and enumeration of transmitted/founder viruses responsible for productive systemic infection. Use of this strategy as a means for identifying transmitted viruses suggested that intrarectal simian immunodeficiency virus (SIV) inoculation of macaques recapitulates key features of human rectal infection. However, no studies have used the SGA strategy to identify vaginally transmitted virus(es) in macaques or to determine how early SIV diversification in vaginally infected animals compares with HIV-1 in humans. We used SGA to amplify 227 partial env sequences from a SIVmac251 challenge stock and from seven rhesus macaques at the earliest plasma viral RNA-positive time point after low- and high-dose intravaginal inoculation. Sequences were analyzed phylogenetically to determine the relationship of transmitted/founder viruses within and between each animal and the challenge stock. In each animal, discrete low-diversity env sequence lineages were evident, and these coalesced phylogenetically to identical or near-identical env sequences in the challenge stock, thus confirming the validity of the SGA sequencing and modeling strategy for identifying vaginally transmitted SIV. Between 1 and 10 viruses were responsible for systemic infection, similar to humans infected by sexual contact, and the set of viruses transmitted to the seven animals studied represented the full genetic constellation of the challenge stock. These findings recapitulate many of the features of sexual HIV-1 transmission in women. Furthermore, the SIV rhesus macaque model can be used to understand the factors that influence the transmission of single versus multiple SIV variants.

Counteraction of HLA-C-mediated immune control of HIV-1 by Nef.

A host genetic variant (-35C/T) correlates with increased human leukocyte antigen C (HLA-C) expression and improved control of HIV-1. HLA-C-mediated immunity may be particularly protective because HIV-1 is unable to remove HLA-C from the cell surface, whereas it can avoid HLA-A- and HLA-B-mediated immunity by Nef-mediated down-modulation. However, some individuals with the protective -35CC genotype exhibit high viral loads. Here, we investigated whether the ability of HIV-1 to replicate efficiently in the "protective" high-HLA-C-expression host environment correlates with specific functional properties of Nef. We found that high set point viral loads (sVLs) were not associated with the emergence of Nef variants that had acquired the ability to down-modulate HLA-C or were more effective in removing HLA-A and HLA-B from the cell surface. However, in individuals with the protective -35CC genotype we found a significant association between sVLs and the efficiency of Nef-mediated enhancement of virion infectivity and modulation of CD4, CD28, and the major histocompatibility complex class II (MHC-II)-associated invariant chain (Ii), while this was not observed in subjects with the -35TT genotype. Since the latter Nef functions all influence the stimulation of CD4(+) T helper cells by antigen-presenting cells, they may cooperate to affect both the activation status of infected T cells and the generation of an antiviral cytotoxic T-lymphocyte (CTL) response. In comparison, different levels of viremia in individuals with the common -35TT genotype were not associated with differences in Nef function but with differences in HLA-C mRNA expression levels. Thus, while high HLA-C expression may generally facilitate control of HIV-1, Nef may counteract HLA-C-mediated immune control in some individuals indirectly, by manipulating T-cell function and MHC-II antigen presentation.

Origin and biology of simian immunodeficiency virus in wild-living western gorillas.

Western lowland gorillas (Gorilla gorilla gorilla) are infected with a simian immunodeficiency virus (SIVgor) that is closely related to chimpanzee and human immunodeficiency viruses (SIVcpz and HIV-1, respectively) in west central Africa. Although existing data suggest a chimpanzee origin for SIVgor, a paucity of available sequences has precluded definitive conclusions. Here, we report the molecular characterization of one partial (BQ664) and three full-length (CP684, CP2135, and CP2139) SIVgor genomes amplified from fecal RNAs of wild-living gorillas at two field sites in Cameroon. Phylogenetic analyses showed that all SIVgor strains clustered together, forming a monophyletic lineage throughout their genomes. Interestingly, the closest relatives of SIVgor were not SIVcpzPtt strains from west central African chimpanzees (Pan troglodytes troglodytes) but human viruses belonging to HIV-1 group O. In trees derived from most genomic regions, SIVgor and HIV-1 group O formed a sister clade to the SIVcpzPtt lineage. However, in a tree derived from 5' pol sequences ( approximately 900 bp), SIVgor and HIV-1 group O fell within the SIVcpzPtt radiation. The latter was due to two SIVcpzPtt strains that contained mosaic pol sequences, pointing to the existence of a divergent SIVcpzPtt lineage that gave rise to SIVgor and HIV-1 group O. Gorillas appear to have acquired this lineage at least 100 to 200 years ago. To examine the biological properties of SIVgor, we synthesized a full-length provirus from fecal consensus sequences. Transfection of the resulting clone (CP2139.287) into 293T cells yielded infectious virus that replicated efficiently in both human and chimpanzee CD4(+) T cells and used CCR5 as the coreceptor for viral entry. Together, these results provide strong evidence that P. t. troglodytes apes were the source of SIVgor. These same apes may also have spawned the group O epidemic; however, the possibility that gorillas served as an intermediary host cannot be excluded.

Conservation of Nef function across highly diverse lineages of SIVsmm.

BACKGROUND: SIVsmm is a simian immunodeficiency virus that persists efficiently without causing disease in naturally infected sooty mangabeys (SMs) but induces AIDS upon cross-species transmission to humans and macaques. Current phylogenetic data indicate that SIVsmm strains comprise a highly diverse group of viruses that can be subdivided into different lineages. Since only certain SIVsmm strains have successfully crossed the species barrier to humans and macaques, the question has been raised whether there are lineage specific differences in SIVsmm biology. In the present study we examined whether representatives of five different SIVsmm lineages show differences in the function of the accessory Nef protein, which plays an important role in viral persistence, transmission and pathogenesis. RESULTS: We found that nef alleles from all SIVsmm lineages down-modulated CD4, MHC-I, CD28 and CD3 and up-regulated the invariant chain (Ii) associated with immature MHC-II molecules in human-derived cells. Moreover, they generally suppressed the responsiveness of virally infected T cells to activation, enhanced virion infectivity and promoted virus replication in human peripheral blood mononuclear cells. The functional activity of these nef alleles in the various assays varied substantially between different strains of SIVsmm but quantitative analyses did not reveal any significant lineage-specific differences in Nef function. CONCLUSION: Nef alleles from different lineages of SIVsmm do not require adaptive changes to be functionally active in human cells. Strain rather than lineage-specific differences in Nef function may impact the virological and immunological feature of SIVsmm in SMs and possibly affected viral fitness and pathogenicity in human and macaque hosts.

Deciphering human immunodeficiency virus type 1 transmission and early envelope diversification by single-genome amplification and sequencing.

Accurate identification of the transmitted virus and sequences evolving from it could be instrumental in elucidating the transmission of human immunodeficiency virus type 1 (HIV-1) and in developing vaccines, drugs, or microbicides to prevent infection. Here we describe an experimental approach to analyze HIV-1 env genes as intact genetic units amplified from plasma virion RNA by single-genome amplification (SGA), followed by direct sequencing of uncloned DNA amplicons. We show that this strategy precludes in vitro artifacts caused by Taq-induced nucleotide substitutions and template switching, provides an accurate representation of the env quasispecies in vivo, and has an overall error rate (including nucleotide misincorporation, insertion, and deletion) of less than 8 x 10(-5). Applying this method to the analysis of virus in plasma from 12 Zambian subjects from whom samples were obtained within 3 months of seroconversion, we show that transmitted or early founder viruses can be identified and that molecular pathways and rates of early env diversification can be defined. Specifically, we show that 8 of the 12 subjects were each infected by a single virus, while 4 others acquired more than one virus; that the rate of virus evolution in one subject during an 80-day period spanning seroconversion was 1.7 x 10(-5) substitutions per site per day; and that evidence of strong immunologic selection can be seen in Env and overlapping Rev sequences based on nonrandom accumulation of nonsynonymous mutations. We also compared the results of the SGA approach with those of more-conventional bulk PCR amplification methods performed on the same patient samples and found that the latter is associated with excessive rates of Taq-induced recombination, nucleotide misincorporation, template resampling, and cloning bias. These findings indicate that HIV-1 env genes, other viral genes, and even full-length viral genomes responsible for productive clinical infection can be identified by SGA analysis of plasma virus sampled at intervals typical in large-scale vaccine trials and that pathways of viral diversification and immune escape can be determined accurately.

Variation in the strength of selected codon usage bias among bacteria.

Among bacteria, many species have synonymous codon usage patterns that have been influenced by natural selection for those codons that are translated more accurately and/or efficiently. However, in other species selection appears to have been ineffective. Here, we introduce a population genetics-based model for quantifying the extent to which selection has been effective. The approach is applied to 80 phylogenetically diverse bacterial species for which whole genome sequences are available. The strength of selected codon usage bias, S, is found to vary substantially among species; in 30% of the genomes examined, there was no significant evidence that selection had been effective. Values of S are highly positively correlated with both the number of rRNA operons and the number of tRNA genes. These results are consistent with the hypothesis that species exposed to selection for rapid growth have more rRNA operons, more tRNA genes and more strongly selected codon usage bias. For example, Clostridium perfringens, the species with the highest value of S, can have a generation time as short as 7 min.

Complete genome analysis of one of the earliest SIVcpzPtt strains from Gabon (SIVcpzGAB2).

Chimpanzees in west central Africa (Pan troglodytes troglodytes) are known to harbor simian immunodeficiency viruses (SIVcpzPtt) that represent the closest relatives of human immunodeficiency virus type 1 (HIV-1); however, the number of SIVcpzPtt strains that have been fully characterized is still limited. Here, we report the complete nucleotide sequence of SIVcpzGAB2, a virus originally identified in 1989 in a chimpanzee (P. t. troglodytes) from Gabon. Analysis of this sequence reveals that SIVcpzGAB2 is a member of the SIVcpzPtt group of viruses, but that it differs from other SIVcpzPtt strains by exhibiting a highly divergent Env V3 loop with an unusual crown (NLSPGTT) containing a canonical N-linked glycosylation site, an unpaired cysteine residue in Env V4, and two late (L) domain motifs (PTAP and YPSL) in Gag p6. Moreover, phylogenetic analyses indicate evidence of recombination during the early divergence of SIVcpzPtt strains; in particular, part of the pol gene sequence of SIVcpzGAB2 appears to be derived from a previously unidentified SIVcpz lineage ancestral to HIV-1 group O. These data indicate extensive diversity among naturally occurring SIVcpzPtt strains and provide new insight into the origin of HIV-1 group O.

Armadillo-repeat protein functions: questions for little creatures.

Armadillo (ARM)-repeat proteins form a large family with diverse and fundamental functions in many eukaryotes. ARM-repeat proteins have largely been characterised in multicellular organisms and much is known about how a subset of these proteins function. The structure of ARM-repeats allows proteins containing them to be functionally very versatile. Are the ARM-repeat proteins in 'little creatures' as multifunctional as their better-studied relatives? The time is now right to start analysing ARM-repeat proteins in these new systems to better understand their cell biology. Here, we review recent advances in understanding the many cellular roles of both well-known and novel ARM-repeat proteins.

The Armadillo repeat protein PF16 is essential for flagellar structure and function in Plasmodium male gametes.

Malaria, caused by the apicomplexan parasite Plasmodium, threatens 40% of the world's population. Transmission between vertebrate and insect hosts depends on the sexual stages of the life-cycle. The male gamete of Plasmodium parasite is the only developmental stage that possesses a flagellum. Very little is known about the identity or function of proteins in the parasite's flagellar biology. Here, we characterise a Plasmodium PF16 homologue using reverse genetics in the mouse malaria parasite Plasmodium berghei. PF16 is a conserved Armadillo-repeat protein that regulates flagellar structure and motility in organisms as diverse as green algae and mice. We show that P. berghei PF16 is expressed in the male gamete flagellum, where it plays a crucial role maintaining the correct microtubule structure in the central apparatus of the axoneme as studied by electron microscopy. Disruption of the PF16 gene results in abnormal flagellar movement and reduced fertility, but does not lead to complete sterility, unlike pf16 mutations in other organisms. Using homology modelling, bioinformatics analysis and complementation studies in Chlamydomonas, we show that some regions of the PF16 protein are highly conserved across all eukaryotes, whereas other regions may have species-specific functions. PF16 is the first ARM-repeat protein characterised in the malaria parasite genus Plasmodium and this study opens up a novel model for analysis of Plasmodium flagellar biology that may provide unique insights into an ancient organelle and suggest novel intervention strategies to control the malaria parasite.

Full-length sequence analysis of SIVmus in wild populations of mustached monkeys (Cercopithecus cephus) from Cameroon provides evidence for two co-circulating SIVmus lineages.

Mustached monkeys (Cercopithecus cephus), which form a significant component of primate bushmeat in west central Africa, are infected with simian immunodeficiency virus (SIVmus). We identified and genetically characterized five new SIVmus strains infecting wild living mustached monkeys from Cameroon. Phylogenetic analysis of partial pol sequences revealed that SIVmus strains form two distinct groups within the clade comprised of lentiviruses isolated from Cercopithecus nictitans (SIVgsn), Cercopithecus mona (SIVmon) and C. cephus (SIVmus). Characterisation of three full-length SIVmus genomes confirmed the presence of two distinct lineages infecting mustached monkeys. These two variants of SIVmus, here designated SIVmus-1 and SIVmus-2, were isolated from animals sharing habitats within the same geographic region. Phylogenetic analyses showed that the diversification of SIVmus, SIVgsn and SIVmon involved inter-lineage recombination, and suggested that one of the SIVmus lineages likely resulted from cross-species transmission and recombination involving SIVmus and an as yet uncharacterized SIV. These results indicate that cross-species transmission and recombination play a major role in the evolution of primate lentiviruses among sympatric primate species.

Adaptation of HIV-1 to its human host.

Human immunodeficiency virus type 1 (HIV-1) originated from three independent cross-species transmissions of simian immunodeficiency virus (SIVcpzPtt) infecting chimpanzees (Pan troglodytes troglodytes) in west central Africa, giving rise to pandemic (group M) and non-pandemic (groups N and O) clades of HIV-1. To identify host-specific adaptations in HIV-1 we compared the inferred ancestral sequences of HIV-1 groups M, N and O to 12 full length genome sequences of SIVcpzPtt and four of the outlying but closely related SIVcpzPts (from P. t. schweinfurthii). This analysis revealed a single site that was completely conserved among SIVcpzPtt strains but different (due to the same change) in all three groups of HIV-1. This site, Gag-30, lies within p17, the gag-encoded matrix protein. It is Met in SIVcpzPtt, underwent a conservative replacement by Leu in one lineage of SIVcpzPts but changed radically to Arg on all three lineages leading to HIV-1. During subsequent diversification this site has been conserved as a basic residue (Arg or Lys) in most lineages of HIV-1. Retrospective analysis revealed that Gag-30 had reverted to Met in a previous experiment in which HIV-1 was passaged through chimpanzees. To examine whether this substitution conferred a species specific growth advantage, we used site-directed mutagenesis to generate variants of these chimpanzee-adapted HIV-1 strains with Lys at Gag-30, and tested their replication in both human and chimpanzee CD4+ T lymphocytes. Remarkably, viruses encoding Met replicated to higher titers than viruses encoding Lys in chimpanzee T cells, but the opposite was found in human T cells. Taken together, these observations provide compelling evidence for host-specific adaptation during the emergence of HIV-1 and identify the viral matrix protein as a modulator of viral fitness following transmission to the new human host.

Genetic diversity and phylogeographic clustering of SIVcpzPtt in wild chimpanzees in Cameroon.

It is now well established that the clade of simian immunodeficiency viruses (SIVs) infecting west central African chimpanzees (Pan troglodytes troglodytes) and western gorillas (Gorilla gorilla gorilla) comprises the progenitors of human immunodeficiency virus type 1 (HIV-1). In this study, we have greatly expanded our previous molecular epidemiological survey of SIVcpz in wild chimpanzees in Cameroon. The new results confirm a wide but uneven distribution of SIVcpzPtt in P. t. troglodytes throughout southern Cameroon and indicate the absence of SIVcpz infection in Pan troglodytes vellerosus. Analyzing 725 fecal samples from 15 field sites, we obtained partial nucleotide sequences from 16 new SIVcpzPtt strains and determined full-length sequences for two of these. Phylogenetic analyses of these new viruses confirmed the previously reported phylogeographic clustering of SIVcpzPtt lineages, with viruses related to the ancestors of HIV-1 groups M and N circulating exclusively in southeastern and south central P. t. troglodytes communities, respectively. Importantly, the SIVcpzPtt strains from the southeastern corner of Cameroon represent a relatively isolated clade indicating a defined geographic origin of the chimpanzee precursor of HIV-1 group M. Since contacts between humans and apes continue, the possibility of ongoing transmissions of SIV from chimpanzees (or gorillas) to humans has to be considered. In this context, our finding of distinct SIVcpzPtt envelope V3 sequence clades suggests that these peptides may be useful for the serological differentiation of SIVcpzPtt and HIV-1 infections, and thus the diagnosis of new cross-species transmissions if they occurred.

Generation of infectious molecular clones of simian immunodeficiency virus from fecal consensus sequences of wild chimpanzees.

Studies of simian immunodeficiency viruses (SIVs) in their endangered primate hosts are of obvious medical and public health importance, but technically challenging. Although SIV-specific antibodies and nucleic acids have been detected in primate fecal samples, recovery of replication-competent virus from such samples has not been achieved. Here, we report the construction of infectious molecular clones of SIVcpz from fecal viral consensus sequences. Subgenomic fragments comprising a complete provirus were amplified from fecal RNA of three wild-living chimpanzees and sequenced directly. One set of amplicons was concatenated using overlap extension PCR. The resulting clone (TAN1.24) contained intact genes and regulatory regions but was replication defective. It also differed from the fecal consensus sequence by 76 nucleotides. Stepwise elimination of all missense mutations generated several constructs with restored replication potential. The clone that yielded the most infectious virus (TAN1.910) was identical to the consensus sequence in both protein and long terminal repeat sequences. Two additional SIVcpz clones were constructed by direct synthesis of fecal consensus sequences. One of these (TAN3.1) yielded fully infectious virus, while the second one (TAN2.69) required modification at one ambiguous site in the viral pol gene for biological activity. All three reconstructed proviruses produced infectious virions that replicated in human and chimpanzee CD4(+) T cells, were CCR5 tropic, and resembled primary human immunodeficiency virus type 1 isolates in their neutralization phenotype. These results provide the first direct evidence that naturally occurring SIVcpz strains already have many of the biological properties required for persistent infection of humans, including CD4 and CCR5 dependence and neutralization resistance. Moreover, they outline a new strategy for obtaining medically important "SIV isolates" that have thus far eluded investigation. Such isolates are needed to identify viral determinants that contribute to cross-species transmission and host adaptation.

Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1.

High-level immune activation and T cell apoptosis represent a hallmark of HIV-1 infection that is absent from nonpathogenic SIV infections in natural primate hosts. The mechanisms causing these varying levels of immune activation are not understood. Here, we report that nef alleles from the great majority of primate lentiviruses, including HIV-2, downmodulate TCR-CD3 from infected T cells, thereby blocking their responsiveness to activation. In contrast, nef alleles from HIV-1 and a subset of closely related SIVs fail to downregulate TCR-CD3 and to inhibit cell death. Thus, Nef-mediated suppression of T cell activation is a fundamental property of primate lentiviruses that likely evolved to maintain viral persistence in the context of an intact host immune system. This function was lost during viral evolution in a lineage that gave rise to HIV-1 and may have predisposed the simian precursor of HIV-1 for greater pathogenicity in humans.

Chimpanzee reservoirs of pandemic and nonpandemic HIV-1.

Human immunodeficiency virus type 1 (HIV-1), the cause of human acquired immunodeficiency syndrome (AIDS), is a zoonotic infection of staggering proportions and social impact. Yet uncertainty persists regarding its natural reservoir. The virus most closely related to HIV-1 is a simian immunodeficiency virus (SIV) thus far identified only in captive members of the chimpanzee subspecies Pan troglodytes troglodytes. Here we report the detection of SIVcpz antibodies and nucleic acids in fecal samples from wild-living P. t. troglodytes apes in southern Cameroon, where prevalence rates in some communities reached 29 to 35%. By sequence analysis of endemic SIVcpz strains, we could trace the origins of pandemic (group M) and nonpandemic (group N) HIV-1 to distinct, geographically isolated chimpanzee communities. These findings establish P. t. troglodytes as a natural reservoir of HIV-1.

Simian immunodeficiency virus infection in free-ranging sooty mangabeys (Cercocebus atys atys) from the Taï Forest, Côte d'Ivoire: implications for the origin of epidemic human immunodeficiency virus type 2.

Simian immunodeficiency virus of sooty mangabeys (SIVsmm) is recognized as the progenitor of human immunodeficiency virus type 2 (HIV-2) and has been transmitted to humans on multiple occasions, yet the epidemiology and genetic diversity of SIVsmm infection in wild-living populations remain largely unknown. Here, we report the first molecular epidemiological survey of SIVsmm in a community of approximately 120 free-ranging sooty mangabeys in the Taï Forest, Côte d'Ivoire. Fecal samples (n = 39) were collected from 35 habituated animals (27 females and 8 males) and tested for SIVsmm virion RNA (vRNA). Viral gag (800 bp) and/or env (490 bp) sequences were amplified from 11 different individuals (eight females and three males). Based on the sensitivity of fecal vRNA detection and the numbers of samples analyzed, the prevalence of SIVsmm infection was estimated to be 59% (95% confidence interval, 0.35 to 0.88). Behavioral data collected from this community indicated that SIVsmm infection occurred preferentially in high-ranking females. Phylogenetic analysis of gag and env sequences revealed an extraordinary degree of genetic diversity, including evidence for frequent recombination events in both the recent and distant past. Some sooty mangabeys harbored near-identical viruses (<2% interstrain distance), indicating epidemiologically linked infections. These transmissions were identified by microsatellite analyses to involve both related (mother/daughter) and unrelated individuals, thus providing evidence for vertical and horizontal transmission in the wild. Finally, evolutionary tree analyses revealed significant clustering of the Taï SIVsmm strains with five of the eight recognized groups of HIV-2, including the epidemic groups A and B, thus pointing to a likely geographic origin of these human infections in the eastern part of the sooty mangabey range.