Although parasite-host co-speciation is a long-held hypothesis, convincing evidence for long-term co-speciation remains elusive, largely because of small numbers of hosts and parasites studied and uncertainty over rates of evolutionary change. Co-speciation is especially rare in RNA viruses, in which cross-species transfer is the dominant mode of evolution. Simian foamy viruses (SFVs) are ubiquitous, non-pathogenic retroviruses that infect all primates. Here we test the co-speciation hypothesis in SFVs and their primate hosts by comparing the phylogenies of SFV polymerase and mitochondrial cytochrome oxidase subunit II from African and Asian monkeys and apes. The phylogenetic trees were remarkably congruent in both branching order and divergence times, strongly supporting co-speciation. Molecular clock calibrations revealed an extremely low rate of SFV evolution, 1.7 x 10(-8) substitutions per site per year, making it the slowest-evolving RNA virus documented so far. These results indicate that SFVs might have co-speciated with Old World primates for at least 30 million years, making them the oldest known vertebrate RNA viruses.

IntroductionThe induction and maintenance of immune responses to antigens is tightly regulated. Activation of T cells requires the interaction between the T-cell receptor and the antigen presented on the surface of an antigen-presenting cell (APC; first signal) and engagement of CD28 (second signal) by the costimulatory molecules B7-1 (CD80) and B7-2 (CD86). 1,2 Costimulation is particularly important for the initial T-cell response, promoting proliferation and survival. Following antigen stimulation, both CD28 and its negative regulatory, cytotoxic T lymphocyte antigen-4 (CTLA-4), are up-regulated on the cell surface and compete for their ligands, B7-1 and B7-2. CTLA-4 binds to both B7-1 and B7-2 with higher (10-to 20-fold) affinity than CD28, 3,4 and, in contrast to CD28, CTLA-4 suppresses T-cell activation. However, competition with CD28 for the costimulatory molecules is not likely to be the main mechanism responsible for CTLA-4 immunoregulatory activity. [5][6][7] Several lines of evidence suggest that expression of CTLA-4 by CD25 ϩ CD4 ϩ regulatory T (T reg ) cells plays a role in controlling peripheral T-cell tolerance and differentiation. 8,9 T reg cells are CD4 ϩ T lymphocytes that express high levels of the interleukin-2 (IL-2) receptor ␣-chain (CD25), and constitutively express CTLA-4. T reg cells inhibit the proliferation of T cells through contactdependent or cytokine-mediated (IL-10, transforming growth factor-␤ [TGF-␤]) inhibition of T-cell responses. 10 T reg cells can induce activation of the enzyme IDO in APCs via CTLA-4-mediated ligation of CD80/CD86. 11,12 IDO confers immunosuppressive activity to APCs. 11,12 Two mechanisms have been suggested as mediators of the T-cellsuppressive action of IDO 13 : degradation and consequent reduction of tryptophan, an essential amino acid required for T-cell proliferation; and generation of inhibitory tryptophan metabolites. Blocking CTLA-4 signals with monoclonal antibodies may provide an important tool to influence the host immune response in clinical settings. For example, synergy between anti-CD25 and anti-CTLA-4 monoclonal antibodies has been shown to be effective in antitumor therapy. 14,15 T reg cells may suppress a potentially successful adaptive host immune response to a pathogen. [16][17][18][19][20][21] In the case of HIV infection, CTLA-4 expression is higher in patients with advanced clinical symptoms compared with asymptomatic individuals, 22,23 and the frequency of CTLA-4-expressing CD25 ϩ CD4 ϩ T reg cells is increased in lymphoid tissues in untreated individuals infected with HIV-1. 24 Primary infection of macaques with simian immunodeficiency virus (SIV) is associated with an increase in T reg cells, IDO, TGF-␤, and IL-10. 25 Similarly, chronic SIV infection is associated with an accumulation of T reg cells in lymphoid tissues, including the gut, and an increased level of immunosuppressive cytokines (A. B., M. V., A. H., D. F., J. N., Valentina Cecchinato, G. F., G. M. S., and C. C., our unpublished results, October 2006).Here, we examined...

We describe the first reported transmission to a human of simian foamy virus (SFV) from a free-ranging population of nonhuman primates in Asia. The transmission of an exogenous retrovirus, SFV, from macaques ( Macaca fascicularis ) to a human at a monkey temple in Bali, Indonesia, was investigated with molecular and serologic techniques. Antibodies to SFV were detected by Western blotting of serum from 1 of 82 humans tested. SFV DNA was detected by nested polymerase chain reaction (PCR) from the blood of the same person. Cloning and sequencing of PCR products confirmed the virus's close phylogenetic relationship to SFV isolated from macaques at the same temple. This study raises concerns that persons who work at or live around monkey temples are at risk for infection with SFV.

Simian foamy viruses (SFVs) belong to a genetically and antigenically diverse class of retroviruses that naturally infect a wide range of nonhuman primates (NHPs) and can also be transmitted to humans occupationally exposed to NHPs. Current serologic detection of SFV infection requires separate Western blot (WB) testing by using two different SFV antigens [SFV(AGM) (African green monkey) and SFV(CPZ) (chimpanzee)]. However, this method is labor intensive and validation is limited to only small numbers of NHPs. To facilitate serologic SFV testing, we developed a WB assay that combines antigens from both SFV(AGM) and SFV(CPZ). The combined-antigen WB (CA-WB) assay was validated with 145 serum samples from 129 NHPs (32 African and Asian species) and 16 humans, all with known SFV infection status determined by PCR. Concordant CA-WB results were obtained for all 145 PCR-positive or -negative primate and human specimens, giving the assay a 100% sensitivity and specificity. In addition, no reactivity was observed in sera from persons positive for human immunodeficiency virus or human T cell lymphotropic virus (HIV/HTLV) (n = 25) or HIV/HTLV-negative U.S. blood donors (n = 100). Using the CA-WB assay, we screened 360 sera from 43 Old World primate species and found an SFV prevalence of about 68% in both African and Asian primates. We also isolated SFV from the blood of four seropositive primates (Allenopithecus nigroviridis, Trachypithecus françoisi, Hylobates pileatus, and H. leucogenys) not previously known to be infected with SFV. Phylogenetic analysis of integrase sequences from these isolates confirmed that all four SFVs represent new, distinct, and highly divergent lineages. These results demonstrate the ability of the CA-WB assay to detect infection in a large number of NHP species, including previously uncharacterized infections with divergent SFVs.