Baboon Endogenous Virus Research Articles

Viral metagenomic analysis reveals potential biological hazards in non‐human primates in a zoo

AbstractPathogens have been documented to be transmissible between humans and non‐human primates (NHPs), with NHPs demonstrating susceptibility to human viruses. Conducting surveillance for viruses in NHPs to identify potential zoonotic agents that may emerge or pose a high risk of spillover remains a critical strategy for preparing for and responding to future zoonotic events. This study employed viral metagenomic analysis on nine randomly selected NHPs from the Zoo in China to detect potential pathogens within captive environments. The analysis identified the presence of picornavirus Encephalomyocarditis virus (EMCV), poxvirus (BeAn 58,058 virus, BAV), and retroviruses (human endogenous retrovirus, HERV and baboon endogenous virus, BaEV). These viruses exhibited significant genetic homology to established viral strains, with EMCV demonstrating close relatedness to a strain previously detected in the United States, and BAV beling newly identified in NHPs. The study suggests that zoo rodents, particularly rats, serve as the primary reservoirs for the viruses, thereby posing a potential threat to public health. Therefore, this underscores the imperative to enhance rodent control measures within zoological institutions and provides strategic recommendations for mitigating interspecies viral transmission.

CD44v6 specific CAR-NK cells for targeted immunotherapy of head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a major challenge for current therapies. CAR-T cells have shown promising results in blood cancers, however, their effectiveness against solid tumors remains a hurdle. Recently, CD44v6-directed CAR-T cells demonstrated efficacy in controlling tumor growth in multiple myeloma and solid tumors such as HNSCC, lung and ovarian adenocarcinomas. Apart from CAR-T cells, CAR-NK cells offer a safe and allogenic alternative to autologous CAR-T cell therapy. In this paper, we investigated the capacity of CAR-NK cells redirected against CD44v6 to execute cytotoxicity against HNSCC. Anti-CD44v6 CAR-NK cells were generated from healthy donor peripheral blood-derived NK cells using gamma retroviral vectors (gRVs). The NK cell transduction was optimized by exploring virus envelope proteins derived from the baboon endogenous virus envelope (BaEV), feline leukemia virus (FeLV, termed RD114-TR) and gibbon ape leukemia virus (GaLV), respectively. BaEV pseudotyped gRVs induced the highest transduction rate compared to RD114-TR and GaLV envelopes as measured by EGFP and surface CAR expression of transduced NK cells. CAR-NK cells showed a two- to threefold increase in killing efficacy against various HNSCC cell lines compared to unmodified, cytokine-expanded primary NK cells. Anti-CD44v6 CAR-NK cells were effective in eliminating tumor cell lines with high and low CD44v6 expression levels. Overall, the improved cytotoxicity of CAR-NK cells holds promise for a therapeutic option for the treatment of HNSCC. However, further preclinical trials are necessary to test in vivo efficacy and safety, as well to optimize the treatment regimen of anti-CD44v6 CAR-NK cells against solid tumors.

Contemporary Distribution, Estimated Age, and Prehistoric Migrations of Old World Monkey Retroviruses.

Old World monkeys (OWM), simians inhabiting Africa and Asia, are currently affected by at least four infectious retroviruses, namely, simian foamy virus (SFV), simian immunodeficiency virus (SIV), simian T-lymphotropic virus (STLV), and simian type D retrovirus (SRV). OWM also show chromosomal evidence of having been infected in the past with four more retroviral species, baboon endogenous virus (BaEV), Papio cynocephalus endogenous virus (PcEV), simian endogenous retrovirus (SERV), and Rhesus endogenous retrovirus-K (RhERV-K/SERV-K1). For some of the viruses, transmission to other primates still occurs, resulting, for instance, in the HIV pandemic. Retroviruses are intimately connected with their host as they are normally spread by close contact. In this review, an attempt to reconstruct the distribution and history of OWM retroviruses will be made. A literature overview of the species infected by any of the eight retroviruses as well as an age estimation of the pathogens will be given. In addition, primate genomes from databases have been re-analyzed for the presence of endogenous retrovirus integrations. Results suggest that some of the oldest retroviruses, SERV and PcEV, have travelled with their hosts to Asia during the Miocene, when a higher global temperature allowed simian expansions. In contrast, younger viruses, such as SIV and SRV, probably due to the lack of a primate continuum between the continents in later times, have been restricted to Africa and Asia, respectively.

GMP-compliant, automated process for generation of CAR NK cells in a closed system for clinical use

Background & Aim Major advances have been made in harnessing natural killer (NK) cells in cancer immunotherapy in recent years. Regulated by their germ-line encoded activating and inhibitory receptors, NK cells can recognize and eliminate tumor cells rapidly without prior sensitization. Clinical evidence has shown that donor-derived NK cells have low risk in inducing graft-versus-host-disease (GvHD) as well as a reduced risk of life-threatening cytokine storms during therapy. Both properties make NK cells ideal for allogeneic application. To enhance the anti-tumor specificity and efficiency, NK cells can be further modified by chimeric antigen receptors (CARs). Promising clinical outcome of CAR-engineered NK cells has been recently reported for patients with relapsed or refractory B cell malignancies. Methods, Results & Conclusion In this study purified NK cells were cultivated with a feeder cell-free protocol including cytokines in NK MACS GMP Medium. For generation of CAR NK cells we used a Baboon endogenous virus (BaEV)-pseudotyped lentiviral vector system to efficiently transduce NK cells with various CARs and routinely obtained transduction efficiencies between 30-70%. To facilitate the clinical application of CAR NK cells, we implemented this protocol into a highly efficient, automated process to generate CAR NK cells under good manufacturing practice (GMP)-compliant conditions in a closed system by using CliniMACS Prodigy device. The process covers the complete procedure of NK cell manufacturing, including separation, activation, gene modification, and expansion/cultivation. High purity of NK cells (mean 94%) could be achieved by CD3 depletion followed by subsequent CD56 enrichment, resulting in a mean log depletion of T cells of 4.3. Inhouse evaluation runs with leukapheresis products (n=11) achieved a mean transduction efficiency of 52.0% CAR+ cells, resulting in 5.2 – 17.9 x 108 (mean 7.17 x 108) CAR+ NK cells after 14 days of culture. In summary, we developed a novel process for automated NK cell purification, transduction, and cultivation in a closed GMP-compatible system. The high level of automation enables standardized, consistent, and operator independent genetic engineering of NK cells for therapeutic applications.

A Novel BaEVRless-Pseudotyped γ-Globin Lentiviral Vector Drives High and Stable Fetal Hemoglobin Expression and Improves Thalassemic Erythropoiesis In Vitro.

It has previously been demonstrated that the self-inactivating γ-globin lentiviral vector GGHI can significantly increase fetal hemoglobin (HbF) in erythroid cells from thalassemia patients and thus improve the disease phenotype in vitro. In the present study, the GGHI vector was improved further by incorporating novel enhancer elements and also pseudotyping it with the baboon endogenous virus envelope glycoprotein BaEVRless, which efficiently and specifically targets human CD34+ cells. We evaluated the hypothesis that the newly constructed vector designated as GGHI-mB-3D would increase hCD34+ cell tropism and thus transduction efficiency at low multiplicity of infection, leading to increased transgene expression. High and stable HbF expression was demonstrated in thalassemic cells for the resulting GGHI-mB-3D/BaEVRless vector, exhibiting increased transduction efficiency compared to the original GGHI-mB-3D/VSVG vector, with a concomitant 91% mean HbF increase at a mean vector copy number per cell of 0.86 and a mean transduction efficiency of 56.4%. Transduced populations also exhibited a trend toward late erythroid, orthochromatic differentiation and reduced apoptosis, a further indication of successful gene therapy treatment. Monitoring expression of ATG5, a key link between autophagy and apoptosis, it was established that this correction correlates with a reduction of enhanced autophagy activation, a typical feature of thalassemic polychromatophilic normoblasts. This work provides novel mechanistic insights into gene therapy-mediated correction of erythropoiesis and demonstrates the beneficial role of BaEVRless envelope glycoprotein compared to VSVG pseudotyping and of the novel GGHI-mB-3D/BaEVRless lentiviral vector for enhanced thalassemia gene therapy.

Suppression of production of baboon endogenous virus by dominant negative mutants of cellular factors involved in multivesicular body sorting pathway

Baboon endogenous virus (BaEV) is an infectious endogenous gammaretrovirus isolated from a baboon placenta. BaEV-related sequences have been identified in both Old World monkeys and African apes, but not in humans or Asian apes. Recently, it was reported that BaEV-like particles were produced from Vero cells derived from African green monkeys by chemical induction, and thus BaEV-like particles may contaminate biological products manufactured using Vero cells. In this study, we constructed an infectious molecular clone of BaEV strain M7. We found two putative L-domain motifs, PPPY and PSAP, in the pp15 region of Gag. To examine the function of the L-domain motifs, we conducted virus budding assay using L-domain motif mutants. We revealed that the PPPY motif, but not the PSAP motif, plays a major role as the L-domain in BaEV budding. We also demonstrated that Vps4A/B are involved in BaEV budding. These data suggest that BaEV Gag recruits the cellular endosomal sorting complex required for transport (ESCRT) machinery through the interaction of the PPPY L-domain with cellular factors. These data will be useful for controlling contamination of BaEV-like particles in biological products in the future.

Chemical Induction of Endogenous Retrovirus Particles from the Vero Cell Line of African Green Monkeys

Endogenous retroviral sequences are present in high copy numbers in the genomes of all species and may be expressed as RNAs; however, the majority are defective for virus production. Although virus has been isolated from various Old World monkey and New World monkey species, there has been no report of endogenous retroviruses produced from African green monkey (AGM) tissues or cell lines. We have recently developed a stepwise approach for evaluating the presence of latent viruses by chemical induction (Khan et al., Biologicals 37:196-201, 2009). Based upon this strategy, optimum conditions were determined for investigating the presence of inducible, endogenous retroviruses in the AGM-derived Vero cell line. Low-level reverse transcriptase activity was produced with 5-azacytidine (AzaC) and with 5'-iodo-2'-deoxyuridine (IUdR); none was detected with sodium butyrate. Nucleotide sequence analysis of PCR-amplified fragments from the gag, pol, and env regions of RNAs, prepared from ultracentrifuged pellets of filtered supernatants, indicated that endogenous retrovirus particles related to simian endogenous type D betaretrovirus (SERV) sequences and baboon endogenous virus type C gammaretrovirus (BaEV) sequences were induced by AzaC, whereas SERV sequences were also induced by IUdR. Additionally, sequence heterogeneity was seen in the RNAs of SERV- and BaEV-related particles. Infectivity analysis of drug-treated AGM Vero cells showed no virus replication in cell lines known to be susceptible to type D simian retroviruses (SRVs) and to BaEV. The results indicated that multiple, inducible endogenous retrovirus loci are present in the AGM genome that can encode noninfectious, viruslike particles.

Baboon Bone-Marrow Xenotransplant in a Patient with Advanced HIV Disease: Case Report and 8-Year Follow-Up

Xenotransplantation offers a solution to the shortage of organ donors and may offer resistance to human-specific pathogens. Baboons are resistant to productive infection with HIV-1. A baboon bone-marrow transplant (BMT) was performed in an attempt to reconstitute the immune system of a patient with advanced AIDS. The aims of this pilot study were to evaluate the safety of the procedure and develop an approach to prevent and monitor for xenozoonoses. A source animal was selected on the basis of infectious disease surveillance protocols. Baboon bone marrow, engineered to remove graft-versus-host-disease-producing mature lineages, but to retain hematopoietic stem cells and facilitating cells, was infused into the patient after nonmyeloablative conditioning. Serial clinical, virologic, immunologic, and hematologic evaluations were performed. A 38-year-old male with advanced AIDS, who had failed to respond to triple-drug antiretroviral therapy, underwent baboon BMT in 1995. The patient tolerated the procedure without complication. Baboon cells were detected in the peripheral blood on days 5 and 13 after transplantation. Baboon endogenous virus (BaEV) was detected on day 5 but not subsequently. Antibody to BaEV was not detected. HIV-1 viral load declined 1.5 log and remained low until 11 months. The patient improved clinically, and no adverse events occurred. The patient is alive 8 years after the procedure. Baboon BMT to treat AIDS was attempted using nonmyeloablative conditioning and resulted in transient microchimerism and clinical and virologic improvements. Long-term improvement was not achieved; however, no adverse events occurred, and no evidence of transmission of xenogeneic infections was found.

Exchange of genetic sequences of long terminal repeat and the env gene by a promiscuous primate type D retrovirus

Squirrel monkey retrovirus (SMRV) is a New World primate type D retrovirus. It was shown that SMRV-related sequences could be detected in another New World species, the skunk. It was further suggested that SMRV and an Old World primate type C retrovirus, baboon endogenous virus (BaEV), may have exchanged their env gene sequences. In this study, we sought to understand which sequences were exchanged between the genomic DNAs of SMRV and skunk. We also sought to determine the sequences exchanged between SMRV and BaEV. Here, we demonstrate that the long terminal repeat of SMRV is present in the skunk genome. We also show, by nucleotide sequence analysis, that the env gene that encodes the p15E glycoprotein of BaEV was most likely transduced from the corresponding gene of a primate type D retrovirus. Our results demonstrate that SMRV is a promiscuous virus with its pol gene homologous to the pol genes of type A, type B and avian type C viruses and a portion of its env gene homologous to the env genes of primate type C retroviruses. However, the primer binding sequence is unique to type D retroviruses. These kinds of recombination are likely to occur more than once in the evolution of retroviruses. The promiscuous nature of retroviruses and the recent incidence of unintended retroviral integration into a gene therapy patient underscore the importance of understanding how retroviral sequences are recombined among themselves and how they are integrated into the mammalian genome.

N-linked glycosylation and sequence changes in a critical negative control region of the ASCT1 and ASCT2 neutral amino acid transporters determine their retroviral receptor functions.

A widely dispersed interference group of retroviruses that includes the feline endogenous virus (RD114), baboon endogenous virus (BaEV), human endogenous virus type W (HERV-W), and type D primate retroviruses uses the human Na(+)-dependent neutral amino acid transporter type 2 (hASCT2; gene name, SLC1A5) as a common cell surface receptor. Although hamster cells are fully resistant to these viruses and murine cells are susceptible only to BaEV and HERV-W pseudotype viruses, these rodent cells both become highly susceptible to all of the viruses after treatment with tunicamycin, an inhibitor of protein N-linked glycosylation. A partial explanation for these results was recently provided by findings that the orthologous murine transporter mASCT2 is inactive as a viral receptor, that a related (ca. 55% identity) murine paralog (mASCT1; gene name, SLC1A4) mediates infections specifically of BaEV and HERV-W, and that N-deglycosylation of mASCT1 activates it as a receptor for all viruses of this interference group. Because the only two N-linked oligosaccharides in mASCT1 occur in the carboxyl-terminal region of extracellular loop 2 (ECL2), it was inferred that this region contributes in an inhibitory manner to infections by RD114 and type D primate viruses. To directly and more thoroughly investigate the receptor active sites, we constructed and analyzed a series of hASCT2/mASCT2 chimeras and site-directed mutants. Our results suggest that a hypervariable sequence of 21 amino acids in the carboxyl-terminal portion of ECL2 plays a critical role in determining the receptor properties of ASCT2 proteins for all viruses in this interference group. In addition, we analyzed the tunicamycin-dependent viral susceptibility of hamster cells. In contrast to mASCT1, which contains two N-linked oligosaccharides that partially restrict viral infections, hamster ASCT1 contains an additional N-linked oligosaccharide clustered close to the others in the carboxyl-terminal region of ECL2. Removal of this N-linked oligosaccharide by mutagenesis enabled hamster ASCT1 to function as a receptor for all viruses of this interference group. These results strongly suggest that combinations of amino acid sequence changes and N-linked oligosaccharides in a critical carboxyl-terminal region of ECL2 control retroviral utilization of both the ASCT1 and ASCT2 receptors.

Serum antibodies reactive with non-human primate retroviruses identified in acute onset schizophrenia.

Schizophrenia is a pervasive neuropsychiatric disease of uncertain etiology. Previous studies have postulated that retroviruses may contribute to the etiology of some cases of schizophrenia. We examined the possible relationship between retroviral infection and schizophrenia by measuring antibodies to a number of different primate retroviruses in the sera of individuals undergoing their first hospitalization for this disease. Sera from patients with first onset schizophrenia and matched healthy controls were analyzed by immunoblot and enzyme linked immunosorbent assays using purified retrovirus antigens to identify and quantify antibodies reactive with retrovirus proteins. A significantly increased incidence of antibodies reactive to gag encoded proteins of Mason-Pfizer monkey virus (MPMV), baboon endogenous virus (BaEV) and simian retrovirus type 5 (SRV-5) was observed in the sera of schizophrenia patients compared to controls. The reactivity of the cases and controls displayed the greatest differences in terms of antibodies to the proteins of Mason-Pfizer monkey virus. Employing an algorithm of enzyme linked immunosorbent assay reactivity followed by immunoblot confirmation, we found that MPMV antibodies in 28.9% of the individuals with first episode schizophrenia patients as compared to 3.7% of the unaffected controls (P<0.009, Fisher's Exact Test). These studies are consistent with the occurrence of retrovirus replication in some individuals who are undergoing their first episode of schizophrenia.

Discovery of a new endogenous type C retrovirus (FcEV) in cats: evidence for RD-114 being an FcEV(Gag-Pol)/baboon endogenous virus BaEV(Env) recombinant.

Analysis of a cat genomic DNA library showed that cats harbor a previously unrecognized endogenous type C retrovirus, whose env gene has homology to the murine Fv-4 resistance gene. This unique retrovirus, designated FcEV (Felis catus endogenous retrovirus), has a type C pol gene, closely related to the primate Papio cynocephalus endogenous virus (PcEV) pol, not overlapping the env gene, unlike in other type C retroviruses, and is presumably present in a higher copy number than RD-114. Phylogenetic analysis of FcEV and RD-114 fragments amplified from cat species and comparison with baboon endogenous virus (BaEV) fragments from monkeys suggested that RD-114 does not represent the cat strain of BaEV but is actually a new recombinant between FcEV type C genes and the env gene of BaEV. Although BaEV did appear to have infected an ancestor of the domestic cat lineage, it was a de novo recombinant that made its way into the cat germ line.

Novel endogenous type C retrovirus in baboons: complete sequence, providing evidence for baboon endogenous virus gag-pol ancestry.

A complete endogenous type C viral genome has been isolated from a baboon genomic library. The provirus, Papio cynocephalus endogenous retrovirus (PcEV), is 8,572 nucleotides long, and 38 to 59 proviral copies per baboon genome are found. The PcEV provirus possesses the typical simple retroviral gene organization, including two long terminal repeats and genes encoding gag, pol, and env proteins. The open reading frames for gag-pol and env are complete but have premature stop codons or frameshift mutations. The primer binding site of PcEV is complementary to tRNAGly. The gag and pol genes of PcEV are closely related to those of the baboon endogenous virus (BaEV). The env coding region of PcEV is related to the env genes of type C retroviruses. This suggests that PcEV is one of the ancestors of BaEV contributing the type C gag-pol genome fragment to the type C/D recombinant virus BaEV. Earlier it was shown that another endogenous type D virus (simian endogenous retrovirus) provided the env gene for BaEV (A. C. van der Kuyl et al., J. Virol. 71:3666-3676, 1997).

A sodium-dependent neutral-amino-acid transporter mediates infections of feline and baboon endogenous retroviruses and simian type D retroviruses.

The type D simian retroviruses cause immunosuppression in macaques and have been reported as a presumptive opportunistic infection in a patient with AIDS. Previous evidence based on viral interference has strongly suggested that the type D simian viruses share a common but unknown cell surface receptor with three type C viruses: feline endogenous virus (RD114), baboon endogenous virus, and avian reticuloendotheliosis virus. Furthermore, the receptor gene for these viruses has been mapped to human chromosome 19q13.1-13.2. We now report the isolation and characterization of a cell surface receptor for this group of retroviruses by using a human T-lymphocyte cDNA library in a retroviral vector. Swiss mouse fibroblasts (NIH 3T3), which are naturally resistant to RD114, were transduced with the retroviral library and then challenged with an RD114-pseudotyped virus containing a dominant selectable gene for puromycin resistance. Puromycin selection yielded 12 cellular clones that were highly susceptible to a beta-galactosidase-encoding lacZ(RD114) pseudotype virus. Using PCR primers specific for vector sequences, we amplified a common 2.9-kb product from 10 positive clones. Expression of the 2.9-kb cDNA in Chinese hamster ovary cells conferred susceptibility to RD114, baboon endogenous virus, and the type D simian retroviruses. The 2.9-kb cDNA predicted a protein of 541 amino acids that had 98% identity with the previously cloned human Na+-dependent neutral-amino-acid transporter Bo. Accordingly, expression of the RD114 receptor in NIH 3T3 cells resulted in enhanced cellular uptake of L-[3H]alanine and L-[3H]glutamine. RNA blot (Northern) analysis suggested that the RD114 receptor is widely expressed in human tissues and cell lines, including hematopoietic cells. The human Bo transporter gene has been previously mapped to 19q13.3, which is closely linked to the gene locus of the RD114 receptor.

The RD114/simian type D retrovirus receptor is a neutral amino acid transporter

The RD114/simian type D retroviruses, which include the feline endogenous retrovirus RD114, all strains of simian immunosuppressive type D retroviruses, the avian reticuloendotheliosis group including spleen necrosis virus, and baboon endogenous virus, use a common cell-surface receptor for cell entry. We have used a retroviral cDNA library approach, involving transfer and expression of cDNAs from highly infectable HeLa cells to nonpermissive NIH 3T3 mouse cells, to clone and identify this receptor. The cloned cDNA, denoted RDR, is an allele of the previously cloned neutral amino acid transporter ATB0 (SLC1A5). Both RDR and ATB0 serve as retrovirus receptors and both show specific transport of neutral amino acids. We have localized the receptor by radiation hybrid mapping to a region of about 500-kb pairs on the long arm of human chromosome 19 at q13.3. Infection of cells with RD114/type D retroviruses results in impaired amino acid transport, suggesting a mechanism for virus toxicity and immunosuppression. The identification and functional characterization of this retrovirus receptor provide insight into the retrovirus life cycle and pathogenesis and will be an important tool for optimization of gene therapy using vectors derived from RD114/type D retroviruses.

Immunosuppression by retroviruses: implications for xenotransplantation.

Retroviruses induce in the infected host an immunosuppression the severity of which depends on the viral load. A pronounced immunosuppression is induced by human and simian immunodeficiency viruses (HIV and SIV) ultimately leading to AIDS. It is very likely that HIV originated by trans-species transmission from primates. In contrast, SIVs are not pathogenic for their natural hosts probably as the result of virus-host coevolution. We have shown that a retroviral protein, the transmembrane envelope protein, may play an important role in retrovirus-induced immunosuppression and that all retroviruses share an evolutionarily highly conserved domain in this protein. We demonstrate that synthetic peptides corresponding to this domain of different retroviruses, including HIV, the baboon endogenous virus (BaEV), and different porcine endogenous retroviruses (PERVs), are immunosuppressive. We provide evidence that BaEV and different PERVs, including those able to grow in human cells, are immunosuppressive for lymphocytes of different species including human. This implies that xenotransplantation may result in a trans-species transmission of endogenous retroviruses derived from the donor animal. In analogy to HIV and SIV high-titer virus replication may cause an AIDS-like disease in the immunosuppressed human transplant recipient. Two additional points have to be considered: First, human anti-complement proteins produced by transgenic animals will also protect the virus and, second, the virus may be transmitted to other humans and thus increase its pathogenic potential.

The risk of using baboons as transplant donors. Exogenous and endogenous viruses.

African nonhuman primates harbor several exogenous and endogenous retroviruses which deserve further consideration in the transplant setting. In particular, simian foamy viruses (SFV), simian T-cell lymphotropic virus (STLV), baboon endogenous virus (BaEV), and simian endogenous retrovirus (SERV) are all carried by baboons and may be transmitted to humans by transplantation. We have found baboons to have high seroprevalence rates to both SFV and STLV, and molecular and serologic methods have been developed to detect such agents. In addition, current nonhuman primate breeding programs have thus far not focused on eliminating these viruses. In summary, the close genetic relationship with humans and number of persistent viral infections in baboons translates into a much greater infectious disease risk when compared to that of other domesticated species.

Amplification of simian retroviral sequences from human recipients of baboon liver transplants.

Investigations into the use of baboons as organ donors for human transplant recipients, a procedure called xenotransplantation, have raised the specter of transmitting baboon viruses to humans and possibly establishing new human infectious diseases. Retrospective analysis of tissues from two human transplant recipients with end-stage hepatic disease who died 70 and 27 days after the transplantation of baboon livers revealed the presence of two simian retroviruses of baboon origin, simian foamy virus (SFV) and baboon endogenous virus (BaEV), in multiple tissue compartments. The presence of baboon mitochondrial DNA was also detected in these same tissues, suggesting that xenogeneic "passenger leukocytes" harboring latent or active viral infections had migrated from the xenografts to distant sites within the human recipients. The persistence of SFV and BaEV in human recipients throughout the posttransplant period underscores the potential infectious risks associated with xenotransplantation.

Complete nucleotide sequence of simian endogenous type D retrovirus with intact genome organization: evidence for ancestry to simian retrovirus and baboon endogenous virus.

A complete endogenous type D viral genome has been isolated from a baboon genomic library. The provirus, simian endogenous retrovirus (SERV), is 8,393 nucleotides long and contains two long terminal repeats and complete genes for gag, pro, pol, and env. The primer binding site is complementary to tRNA(Lys)3, like in lentiviruses. The env GP70 protein is highly homologous to that of baboon endogenous virus (BaEV). PCR analysis of primate DNA showed that related proviral sequences are present in Old World monkeys of the subfamily Cercopithecinae but not in apes and humans. Analysis of virus and host sequences indicated that the proviral genomes were inherited from a common ancestor. Comparison of the evolution of BaEV, exogenous simian retrovirus types 1 to 3 (SRV1 to SRV3), and SERV suggests that SERV is ancestral to both BaEV and the SRVs.

Increased antiretroviral antibody reactivity in sera from a defined population of patients with systemic lupus erythematosus. Correlation with autoantibodies and clinical manifestations.

The implied role of retroviruses in the pathogenesis of murine systemic lupus erythematosus (SLE) led us to study antiretroviral antibodies in a population-based SLE cohort. Immunoassays using whole virus and synthetic peptides were performed on sera from 72 patients with SLE and 88 control subjects. Reactions with whole baboon endogenous virus occurred more frequently in patients with SLE, and correlated with the presence of anti-RNP and anti-Sm. Some retroviral env and gag peptides, several of which were similar to U1 small nuclear RNP, reacted more strongly in patients with SLE, and their presence was correlated with discoid rash, hematologic disorder, and other symptoms. These results provide circumstantial evidence for involvement of retroviruses in the pathogenesis of human SLE; further studies should be carried out using other techniques for measurement of retroviral expression.