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Non-human primates (NHPs) are natural hosts for exogenous retroviruses such as STLV-1 (Simian T-cell Leukemia Virus type 1) and SFV (Simian Foamy Virus), and natural cases of co-infections have been reported (SFV/STLV-1). As described for HTLV-1 in humans, STLV-1 is the etiologic agent of ATL (Adult T cell Leukemia) in NHPs, but the majority of infected animals remain asymptomatic. Furthermore, as for HTLV-1, which is able to replicate through clonal expansion of infected cells, the quantification of the proviral load together with the identification of proviral integration sites in STLV-1-infected NHPs have highlighted the clonal expansion of STLV-1 in vivo (Turpin et al., 2017). On the other hand, SFV is considered as non-pathogenic, but whether co-infections might regulate SFV replication is unknown. The aim of the project is to evaluate the influence of STLV-1 on the proviral load and the retroviral clonality of SFV in naturally infected baboons. First, we have reported that the SFV proviral load increases in the blood of baboons naturally co-infected with SFV and STLV-1 (Alais et al., 2018). We next demonstrate for the first time that SFV is able to replicate by clonal expansion of infected cells in vivo, as described for HTLV-1 and STLV-1. However, STLV-1 does not seem to promote clonal expansion of SFV in vivo. Lastly, in order to analyze if one unique cell can be co-infected by both SFV and STLV-1 in vivo, we develop a DNA-FISH (fluorescence in situ hybridization) approach. Altogether, this work sheds light on the replication of SFV in naturally infected NHPs, and emphasizes the fact that co-infection can significantly impact the replication of exogenous viruses in vivo, Les primates non-humains (PNH) sont les hôtes naturels de plusieurs rétrovirus exogènes tels que STLV-1 (virus de la leucémie simienne de type 1) et SFV (virus foamy simien), et certains cas de co-infections naturelles ont été répertoriés (SFV/STLV-1). Comme HTLV-1 chez l’Homme, STLV-1 est l’agent étiologique de l’ATL (leucémie à cellule T de l’adulte), mais la majorité des PNH infectés restent asymptomatiques. HTLV-1 promeut l’expansion clonale des cellules infectées et l’expansion clonale de STLV-1 a également été démontrée in vivo chez les PNH (Turpin et al., 2017). SFV, lui, provoque une infection asymptomatique, mais aucune donnée n'est disponible quant à la régulation de la réplication de SFV en cas de co-infection. L’objectif du projet consiste à évaluer l’influence de STLV-1 sur la charge provirale (PVL) et la clonalité rétrovirale de SFV chez des babouins naturellement infectés par SFV et STLV-1. Nous avons tout d'abord montré que la PVL de SFV augmente dans le sang des babouins naturellement co-infectés (Alais et al., 2018), par rapport aux animaux infectés uniquement par SFV. Nous avons ensuite démontré que SFV est capable de se répliquer par expansion clonale des cellules infectées in vivo et nos premiers résultats suggèrent que l’expansion clonale de SFV n’est pas favorisée par STLV-1. Enfin, une approche de DNA-FISH (Fluorescence in situ hybridization), nous permettra de déterminer si, in vivo, une même cellule peut être co-infectée par les deux rétrovirus SFV et STLV-1. Ce projet permet d’apporter des informations sur la réplication du virus SFV et met en avant l’influence des co-infections rétrovirales sur la réplication des rétrovirus exogènes in vivo

Viruses are obligate intracellular parasites of the host cells. A commonly accepted view is the requirement of internal membranous structures for various aspects of viral life cycle. Organelles enable favourable intracellular environment for several viruses. However, studies reporting organelle dynamics upon viral infections are scant. In this review, we aim to summarize and highlight modulations caused to various organelles upon viral infection or expression of its proteins.

Hepatitis C Virus belongs to the Flaviviridae family. One proposed mechanism of HCV persistence in the ability to infect hematopoietic cells, including Dendritic cells (DCs). HCV infection of DCs could impair their functions that represent one of the mechanisms, thus hampering viral clearance by the host immune system. Among HCV-encoded proteins, the highly conserved Core protein has been suggested to be responsible for the immunomodulatory properties of this Hepacivirus. Recombinant viral vectors expressing the HCV Core protein and allowing its transduction and therefore the expression of the protein into DCs could be useful tools for the analysis of the properties of the Core protein. Vaccinia Virus and retrovirus have been used to transduce human DCs. Likewise, gene transfer into DCs using Semliki Forest Virus has been reported. This study aimed to express the HCV Core protein in human monocyte-derived DCs using an SFV vector, in which the subgenomic RNA encoding the structural proteins was replaced by the HCV Core sequence and then analyze the effects of its expression on DCs functions.

G Protein Coupled Receptors (GPCRs) constitute the largest membrane protein family represented in the human genome. Their involvement in a wide number of biological processes fully supports their study. GPCR-targeting antibodies are versatile and valuable tools, which remain scarcely available, chiefly because their generation is a challenging process. This thesis presents an alternative and innovative strategy in which recombinant Semliki Forest Virus (SFV) particles coding for the receptor of interest are used as immunogens. When applied to the human version of the Adenosine A2A receptor, this method enables to cause the receptor’s overexpression at the surface of the infected animal cells, which generates an immune response. This strategy enables to raise receptor-specific mouse polyclonal serum. It opens a new path towards the generation of monoclonal mouse antibodies. Additionally, it seems to also be a promising approach to develop nanobodies., Les Récepteurs Couplés aux Protéines G (RCPG) constituent la plus grande famille de protéines membranaires chez l’Homme, et leur implication dans un grand nombre de processus physiologiques justifie pleinement l’intérêt de leur étude. Les anticorps spécifiques de ces récepteurs sont des outils polyvalents à haute valeur ajoutée, qui restent toutefois encore trop rarement disponibles, notamment en raison des difficultés techniques posées par leur génération. Ce manuscrit présente la mise au point d’une méthode d’immunisation alternative et innovante, mettant en jeu des particules virales recombinantes dérivées du Virus de la Forêt de Semliki (SFV) codant pour le récepteur d’intérêt. Appliquée au récepteur de l’adénosine A2A humain, l’immunisation permet d’engendrer la surexpression de celui-ci à la surface des cellules de l’animal infecté, et de provoquer l’apparition d’une réponse immunitaire. Cette approche permet d’une part de générer un sérum polyclonal de souris spécifique au récepteur, et ouvre donc une nouvelle voie pour l’obtention d’anticorps monoclonaux murins. Elle semble d’autre part prometteuse pour la génération de nanobodies.

Oncolytic Semliki Forest virus (SFV) has been suggested as a potential candidate for the treatment of glioblastoma and neuroblastoma. However, the oncolytic capacity of SFV is restricted by the anti-viral type-I interferon (IFN) response. The aim of this study was to increase the oncolytic capacity of a microRNA target tagged SFV against glioblastoma by arming it with the Vaccinia-virus-encoded type-I IFN decoy receptor B18R (SFV4B18RmiRT) to neutralize type-I IFN response. Expression of B18R by SFV4B18RmiRT aided neutralization of IFN-β, which was shown by reduced STAT-1 phosphorylation and improved virus spread in plaque assays. B18R expression by SFV4 increased its oncolytic capacity in vitro against murine glioblastoma (CT-2A), regardless of the presence of exogenous IFN-β. Both SFV4B18RmiRT and SFV4miRT treatments controlled tumor growth in mice with syngeneic orthotopic gliomablastoma (CT-2A). However, treatment with SFV4B18RmiRT induced severe neurological symptoms in some mice because of virus replication in the healthy brain. Neither neurotoxicity nor virus replication in the brain was observed when SFV4miRT was administered. In summary, our results indicate that the oncolytic capacity of SFV4 was improved in vitro and in vivo by incorporation of B18R, but neurotoxicity of the virus was increased, possibly due to loss of microRNA targets. Keywords: Semliki Forest virus, SFV, glioblastoma, type I interferon, B18R

It is now known that all human retroviruses have a non-human primate counterpart. It has been reported that the presence of these retroviruses in humans is the result of interspecies transmission. Several authors have described the passage of a simian retrovirus, simian foamy virus (SFV), from primates to humans. To better understand this retroviral "zoonosis" in natural settings, we evaluated the presence of SFV in both captive and wild non-human primates and in humans at high risk, such as hunters and people bitten by a non-human primate, in Gabon, central Africa. A high prevalence of SFV was found in blood samples from non-human primates and in bush meat collected across the country. Mandrills were found to be highly infected with two distinct strains of SFV, depending on their geographical location. Furthermore, samples collected from hunters and non-human primate laboratory workers showed clear, extensive cross-species transmission of SFV. People who had been bitten by mandrills, gorillas and chimpanzees had persistent SFV infection with low genetic drift. Thus, SFV is presumed to be transmitted from non-human primates mainly through severe bites, involving contact between infected saliva and blood. In this review, we summarize and discuss our five-year observations on the prevalence and dissemination of SFV in humans and non-human primates in Gabon.

Interferon inducible transmembrane proteins (IFITMs) are broad‐spectrum antiviral factors. In cell culture the entry of many enveloped viruses, including orthomyxo‐, flavi‐, and filoviruses, is inhibited by IFITMs, though the mechanism(s) involved remain unclear and may vary between viruses. We demonstrate that Sindbis and Semliki Forest virus (SFV), which both use endocytosis and acid‐induced membrane fusion in early endosomes to infect cells, are restricted by the early endosomal IFITM3. The late endosomal IFITM2 is less restrictive and the plasma membrane IFITM1 does not inhibit normal infection by either virus. IFITM3 inhibits release of the SFV capsid into the cytosol, without inhibiting binding, internalization, trafficking to endosomes or low pH‐induced conformational changes in the envelope glycoprotein. Infection by SFV fusion at the cell surface was inhibited by IFITM1, but was equally inhibited by IFITM3. Furthermore, an IFITM3 mutant (Y20A) that is localized to the plasma membrane inhibited infection by cell surface fusion more potently than IFITM1. Together, these results indicate that IFITMs, in particular IFITM3, can restrict alphavirus infection by inhibiting viral fusion with cellular membranes. That IFITM3 can restrict SFV infection by fusion at the cell surface equivalently to IFITM1 suggests that IFITM3 has greater antiviral potency against SFV.

Interferon inducible transmembrane proteins (IFITMs) are broad‐spectrum antiviral factors. In cell culture the entry of many enveloped viruses, including orthomyxo‐, flavi‐, and filoviruses, is inhibited by IFITMs, though the mechanism(s) involved remain unclear and may vary between viruses. We demonstrate that Sindbis and Semliki Forest virus (SFV), which both use endocytosis and acid‐induced membrane fusion in early endosomes to infect cells, are restricted by the early endosomal IFITM3. The late endosomal IFITM2 is less restrictive and the plasma membrane IFITM1 does not inhibit normal infection by either virus. IFITM3 inhibits release of the SFV capsid into the cytosol, without inhibiting binding, internalization, trafficking to endosomes or low pH‐induced conformational changes in the envelope glycoprotein. Infection by SFV fusion at the cell surface was inhibited by IFITM1, but was equally inhibited by IFITM3. Furthermore, an IFITM3 mutant (Y20A) that is localized to the plasma membrane inhibited infection by cell surface fusion more potently than IFITM1. Together, these results indicate that IFITMs, in particular IFITM3, can restrict alphavirus infection by inhibiting viral fusion with cellular membranes. That IFITM3 can restrict SFV infection by fusion at the cell surface equivalently to IFITM1 suggests that IFITM3 has greater antiviral potency against SFV.

Hinweis: Im Zeitraum vom 20.08.2015 bis zum 15.01.2016 war dem Datensatz eine veraltete Version der Dissertation beigefügt. Für wissenschaftliche Zwecke ist ausschließlich die nun beigefügte Version der Dissertation zu nutzen. Die alte Version muss gelöscht werden und darf nicht weiterverbreitet werden. Auf Basis der bislang zur Verfügung stehenden Methoden konnte weder ein effektiver HIV- Impfstoff entwickelt noch der durchschlagende Erfolg bei der Induktion einer anti-Tumorantwort erzielt werden. Aus diesem Grund ist es Aufgabe der Grundlagenforschung, innovative Lösungsansätze bereit zu stellen, um die Effektivität der Vakzinierung zu verbessern. Diesbezüglich zeigte der Einsatz von replikationskompetenten Vektorsystemen erste vielversprechende Ergebnisse im SIV-Primatenmodell. Hinsichtlich dieses Ansatzes war es Ziel dieser Dissertation, ein neues replika- tionskompetentes Impf-Vektor-System basierend auf simianen Foamyviren zu entwickeln, um eine effektive und permanente Immunantwort gegen definierte Antigene stimulieren zu können. Auf der Basis des foamyviralen Vektors pHSRV2/13 (PFV/HFV) erfolgte die Konstruktion von replizierenden PFV-ΔBet-Basisvektoren. In einer ersten Tierversuchsphase konnte durch ballis- tische Applikation der PFV-ΔBet-Deletionsmutanten via Gene Gun eine permanente PFV- gerichtete Antikörperantwort in Hamstern und Mäusen induziert werden. Die Entwicklung eines effektiven viralen Impf-Vektor-Systems bedingte maßgeblich die stabile Expression definierter Antigene unter Kontrolle der viralen Replikation. Durch die gezielte genetische Modifikation der PFV-ΔBet-Basisvektoren konnte eine Palette von Hybridviren mit variablen Replikations- und Antigen-Expressionseigenschaften generiert werden. Dabei war es möglich, eine stabile Expression von GFP und HIV-CTL-Epitopen über einen Zeitraum von 68 Tagen in vitro nachzuweisen. Im Anschluss erfolgte die Immunisierung von Hamstern und Mäusen mit den generierten PFV- HIV-Epitop-Hybridviren. Durch diese Hybridviren konnte eine permanente, PFV-gerichtete Anti- körperantwort über einen Zeitraum von knapp 400 Tagen induziert werden. Darüber hinaus ist es gelungen, die in vivo Replikation der generierten Impf-Vektoren über Re-Isolation des applizierten Impfvirus aus dem Gewebe eines infizierten Hamsters eindeutig nachzuwiesen. Einen endgültigen Beweis für die Funktionalität des generierten Impf-Vektor-Systems lieferte der geführte Nachweis einer induzierten HIV-Epitop-spezifischen T-Zellpopulation im Milzgewebe von immunisierten Mäusen knapp 400 Tage nach Applikation der Hybrid-Impfviren. Dabei wurde eine variable Immunantwort in Abhängigkeit zu den unterschiedlichen Eigenschaften der konstruierten Impf- Vektoren stimuliert. Dadurch konnte bewiesen werden, dass durch die Applikation von replizierenden foamyviralen Impf-Vektoren die Induktion einer starken und permanenten Immunabwehr prinzipiell möglich ist., Attempts to develop a successful HIV vaccine or induce an effective anti-tumor response using the methods available have so far been unsuccessful. The evaluation of innovative strategies aimed at improving the efficacy of vaccination is therefore an important aspect of basic research. Recent studies using replication vector systems in the SIV-primate model have, in this respect, been promising. The aim of this thesis was therefore to develop a novel replication-competent vaccine vector system based on simian foamy viruses able to induce an effective and enduring immune response against defined antigens. Replicating PFV-ΔBet vectors were constructed using the foamy viral vector pHSRV2/13 (PFV/HFV) as a basis. An initial animal experiment demonstrated the induction of a long-lasting PFV-specific antibody response in hamsters and mice by gene gun ballistic application of the PFV-ΔBet deletion mutants. In order to be effective, a vaccine viral vector of this kind requires the stable expression of defined antigens under the control of viral replication. A variety of hybrid viruses with differing replication and antigen expression characteristics were generated by specific genetic modification of the PFV-ΔBet basis vectors. Virus replication and the stable expression of GFP and an HIV-CTL epitope string could be demonstrated for up to 68 days in vitro. Hamsters and mice were therefore inoculated with the PFV-HIV epitope hybrid viruses and a persistent PFV-specific antibody response was observed over a period of nearly 400 days. Furthermore, in vivo replication of the vaccine vectors was demonstrated by re-isolation of the inoculated virus from the tissues of an infected hamster. The functionality of the vaccine vector system was clearly demonstrated by the presence of HIV epitope-specific T-cells in the spleens of mice immunized almost 400 days previously with the hybrid viruses. The strength of the response appeared to depend on the particular characteristics of the vaccine vectors. These data demonstrate that is in principle possible to induce a strong and persisting immunity by application of replicating foamy virus vaccine vectors.

Single chain Fv antibodies (sFvs) have been produced from filamentous bacteriophage libraries obtained from immunised mice. MFE-23, the most characterised of these sFvs, is reactive with carcinoembryonic antigen (CEA), a glycoprotein that is highly expressed in colorectal adenocarcinomas. MFE-23 has been expressed in bacteria and purified in our laboratory for two clinical trials; a gamma camera imaging trial using123I-MFE-23 and a radioimmunoguided surgery trial using125I-MFE-23, where tumour deposits are detected by a hand-held probe during surgery. Both these trials show MFE-23 is safe and effective in localising tumour deposits in patients with cancer. We are now developing fusion proteins which use MFE-23 to deliver a therapeutic moiety; MFE-23::CPG2 targets the enzyme carboxypeptidase G2 (CPG2) for use in the ADEPT (antibody directed enzyme prodrug therapy) system and MFE::TNFα aims to reduce sequestration and increase tumor concentrations of systemically administered TNFα.

Simian foamy viruses (SFV) are exogenous retroviruses present in most if not all nonhuman primate species. Baboons and other African monkey species are known to harbor SFVs, yet there is presently no data in regard to their genetic relationship. Here we studied SFVs from baboons as compared to other SFVs isolated from a Hamlyn's guenon, a patas monkey, and a vervet. By Western blot analysis, the gag precursor proteins (p74/p70) were detected from all SFVs. In addition, the envelope glycoproteins from a vervet isolate (SFV-Agm2) were comparable in size to the env precursor gp130, the exterior glycoprotein (gp70), and the transmembrane protein (gp48) as detected by lentil lectin binding and radioimmunoprecipitation (RIPA). Molecular comparison of PCR amplified products from pol and LTR regions of each SFV demonstrated a close relationship among baboon SFVs while SFVs from patas, Hamlyn's guenon, and vervet clustered together. The baboon viruses only varied by 4% among each other in the LTR region; however, as much as 26% variation was noted when compared to the other African monkey SFVs. To determine the prevalence rate of SFV-Bab in our baboon colony, we employed both Western blotting and PCR analysis. Antibodies to SFV gag precursor proteins were seen in 7 of 10 infants; however, none were positive by PCR, suggesting that these infants were virus negative and that their antibodies were maternal in origin. Only one juvenile (1/10) and all adults (38/38) were infected with SFV. Taken together these results suggest that SFVs have arisen and diverged along with the evolution of their natural hosts. Furthermore, the high prevalence rates to SFV seen in adult baboons strongly suggest a sexual or oral routes of transmission.

Made available in DSpace on 2014-12-03T13:11:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-09-01Bitstream added on 2014-12-03T13:22:33Z : No. of bitstreams: 1 S1516-89132013000500018.pdf: 107013 bytes, checksum: 0a4b1e7c2d2c2bac93af970e5ee6fbc7 (MD5) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) The number of biopharmaceuticals for medical and veterinarian use produced in mammalian cells is increasing year after year. All of them are obtained by stable recombinant cell lines. However, it is recognized that transient gene expression produces high level expression in a short time. In that sense, viral vectors have been extensively used for producing recombinant proteins on lab-scale. Among them, Semliki Forest virus is commonly employed for this purpose. This review discusses the main aspects related to the use of Semliki Forest virus technology as well as its advantages and drawbacks which limit currently its utilization in biopharmaceutical industry on large-scale. Univ Sao Paulo, Escola Politecn, Dept Engn Quim, Lab Celulas Anim, Sao Paulo, Brazil Univ Estadual Paulista Julho de Mesquita Filho, Fac Ciencia & Letras, Dept Ciencias Biol, Assis, SP, Brazil Inst Butantan, Lab Imunol Viral, Sao Paulo, Brazil Inst Pesquisas Tecnol Estado Sao Paulo SA, Nucleo Bionanomanufatura, Lab Biotecnol Ind, Sao Paulo, Brazil Univ Estadual Paulista Julho de Mesquita Filho, Fac Ciencia & Letras, Dept Ciencias Biol, Assis, SP, Brazil FAPESP: 10/52521-6

Nonhuman primates (NHPs) carry retroviruses such as simian immunodeficiency viruses (SIV), simian T-cell lymphotropic viruses (STLV) and simian foamy viruses (SFV). Here, we revisited NHPs from Cambodia to assess the prevalence and diversity of these retroviruses using updated viral detection tools. We screened blood from 118 NHPs consisting of six species (Macaca fascicularis (n = 91), Macaca leonine (n = 8), Presbytis cristata (n = 3), Nycticebus coucang (n = 1), Hylobates pileatus (n = 14), and Pongo pygmaeus) (n = 1) by using a Luminex-based multiplex serology assay that allows the detection of all known SIV/HIV and SFV lineages. We also used highly sensitive PCR assays to detect each simian retrovirus group. Positive PCR products were sequenced and phylogenetically analyzed to infer evolutionary histories. Fifty-three of 118 (44.9%) NHPs tested positive for SFV by serology and 8/52 (15.4%), all from M. fascicularis, were PCR-confirmed. The 8 novel SFV sequences formed a highly supported distinct lineage within a clade composed of other macaque SFV. We observed no serological or molecular evidence of SIV infection among the 118 NHP samples tested. Four of 118 (3.3%) NHPs were PCR-positive for STLV, including one M. fascicularis, one P. cristata, and two H. pileatus. Phylogenetic analyses revealed that the four novel STLV belonged to the PTLV-1 lineage, outside the African radiation of PTLV-1, like all Asian PTLV identified so far. Sequence analysis of the whole STLV-1 genome from a H. pileatus (C578_Hp) revealed a genetic structure characteristic of PTLV. Similarity analysis comparing the STLV-1 (C578_Hp) sequence with prototype PTLVs showed that C578_Hp is closer to PTLV-1s than to all other types across the entire genome. In conclusion, we showed a high frequency of SFV infection but found no evidence of SIV infection in NHPs from Cambodia. We identified for the first time STLV-1 in a P. cristata and in two H. pileatus.

It is now well established that simian immunodeficiency viruses (SIVs) from chimpanzees (SIVcpz) and gorillas (SIVgor) from west Central Africa are at the origin of HIV-1/AIDS. Apes are also infected with other retroviruses, notably simian T-cell lymphotropic viruses (STLVs) and simian foamy viruses (SFVs), that can be transmitted to humans. We discuss the actual knowledge on SIV, STLV and SFV infections in chimpanzees, gorillas, and bonobos. We especially elaborate on how the recent development of non-invasive methods has allowed us to identify the reservoirs of the HIV-1 ancestors in chimpanzees and gorillas, and increased our knowledge of the natural history of SIV infections in chimpanzees. Multiple cross-species events with retroviruses from apes to humans have occurred, but only one transmission of SIVcpz from chimpanzees in south-eastern Cameroon spread worldwide, and is responsible for the actual HIV pandemic. Frequent SFV transmissions have been recently reported, but no human-to-human transmission has been documented yet. Because humans are still in contact with apes, identification of pathogens in wild ape populations can signal which pathogens may be cause risk for humans, and allow the development of serological and molecular assays with which to detect transmissions to humans. Finally, non-invasive sampling also allows the study of the impact of retroviruses and other pathogens on the health and survival of endangered species such as chimpanzees, gorillas, and bonobos.

Despite promising preclinical results of various therapeutic anticancer immunization strategies, these approaches may not be effective enough to eradicate tumors in cancer patients. While most animal models are based on fast-growing transplantable tumors, malignancies in, for example, cervical cancer patients in general develop much more slowly, which may lead to immune suppression and/or immune tolerance. As a consequence, the immunomodulating signal of any therapeutic immunization regimen should be sufficiently potent to overcome this immunocompromised condition. In previous studies, we demonstrated that an experimental vaccine against human papillomavirus (HPV)-induced cervical cancer, based on Semliki Forest virus (SFV), induces robust HPV-specific cellular immune responses in mice. Now we studied whether this strategy is potent enough to also prime a cellular immune response in immune-tolerant HPV transgenic mice, in which CTL activity cannot be induced using protein or DNA vaccines. We demonstrate that, depending on the route of immunization, SFV-expressing HPV16 E6 and E7 indeed has the capacity to induce HPV16 E7-specific cytotoxic T cells in HPV-transgenic mice.

Simian immunodeficiency viruses, simian T-cell lymphotropic viruses, and simian foamy viruses from nonhuman primates have crossed the species barrier to humans at several time points, leading to the HIV and human T lymphotropic virus epidemic and to sporadic cases of human infections with simian foamy viruses, respectively. Efficient infection and spread in humans differs between simian foamy virus, simian lymphotropic virus, and simian immunodeficiency virus, but seems also to differ among the different viruses from the same simian lineage, as illustrated by the different spread of HIV-1 M, N O, P or for the different HIV-2 groups. Among the four HIV-1 groups, only HIV-1 group M has spread worldwide, and the actual diversity within HIV-1 M (subtypes, circulating recombinants) is the result of subsequent evolution and spread in the human population. HIV-2 only spread to some extent in West Africa, and similarly as for HIV-1, the nine HIV-2 groups have also a different epidemic history. Four types of human T lymphotropic virus, type 1 to 4, have been described in humans and for three of them simian counterparts (simian T lymphotropic virus-1, -2,-3) have been identified in multiple nonhuman primate species. The majority of human infections are with human T lymphotropic virus-1, which is present throughout the world as clusters of high endemicity. Humans are susceptible to a wide variety of simian foamy viruses and seem to acquire these viruses more readily than simian immunodeficiency viruses or simian T lymphotropic viruses, but neither signs of disease in humans nor human-to-human transmission of simian foamy virus have been documented yet. The current HIV-1 M epidemic illustrates the impact of a single cross-species transmission. The recent discovery of HIV-1 P, HIV-2 I, new human T lymphotropic virus-1 and -3 variants, as well as simian foamy virus infections in humans in Central Africa, show that our knowledge of genetic diversity and cross-species transmissions of simian retroviruses is still incomplete.