Healthy mangabey monkeys in a colony at the Yerkes Regional Primate Research Center were found to be infected with a retrovirus related to human immunodeficiency virus (HIV). Virus was isolated from peripheral blood cells of 14 of 15 randomly selected mangabeys. All virus-positive animals had antibodies to the mangabey virus at the time of virus isolation and, in a retrospective study, 82% of mangabey serum samples obtained in 1981 had antibodies to the virus. The newly isolated retrovirus is (i) morphologically identical to HIV by electron microscopy; (ii) serologically related to the human virus by enzyme immunoassay, immunoblotting experiments, radioimmunoprecipitation, and neutralization; and (iii) cytopathic for human OKT4+ cells. The mangabey virus also shares these properties with the simian T-lymphotropic virus type III (STLV-III) recently isolated from diseased macaques and from healthy African green monkeys (STLV-IIIAGM). However, the mangabey virus, like STLV-IIIAGM, differs from both HIV and STLV-III in that it apparently does not cause clinical immunodeficiency or disease following natural infection of the host from which it was isolated. Comparison of the virus-host interactions of these isolates may be valuable in defining determinants of pathogenicity for cytopathic retroviruses.
Blockade of the CD40 pathway with anti-CD40 mAb is immunosuppressive in a large animal, preclinical renal transplant model. The potential effect of this therapy on viral immune responses will be important to consider for the design of safe clinical trials.
The PBj14 isolate of simian immunodeficiency virus from sooty mangabey monkeys (SIVSMM-PBj14) is the most acutely pathogenic primate lentivirus so far described, always causing fatal disease in pig-tailed macaques (Macaca nemestrina) within 8 days of inoculation. As a first step in identifying viral genes and gene products that influence pathogenicity, the SIVSMM-PBj14 genome was amplified by the polymerase chain reaction as 5' and 3' genomic halves of 5.1 and 5.8 kilobases, respectively, and molecularly cloned. DNA sequence analysis revealed a high degree of conservation with other SIVs, except for a 22-base-pair duplication in the enhancer region of the viral long terminal repeat which included a second binding site for the transcription factor NF-kappa B. Of six genomic halves examined, four contributed to the formation of infectious virus that induced acute disease and death in pig-tailed macaques as early as 6 days post-inoculation, with pathology, disease syndromes and kinetics indistinguishable from those induced by the uncloned isolate. To our knowledge this is the first example of acute immunodeficiency disease induced by a molecularly defined lentivirus. Furthermore, the molecularly cloned SIVSMM-PBj14 viruses share with the uncloned virus cytopathicity for mangabey CD4+ cells, a property that may correlate with their observed pathogenicity in vivo.
A virus pool isolated from lymphoid tissue of a macaque (PBj) infected for 14 months with SIV/SMM was found to be associated with acute disease and death. Six of six pig-tailed macaques, one of three rhesus macaques, and three of four SIV/SMM-seronegative mangabeys developed acute disease within 5 days and died from 7 to 13 days postinoculation; however, neither of two SIV/SMM-infected mangabeys died or developed disease. The virus associated with acute disease and death was shown by electron microscopy to be a lentivirus and was serologically indistinguishable from SIV/SMM by immunofluorescence and radioimmunoprecipitation assays. A biologic clone generated from lymphoid tissue of an animal that died 7 days after inoculation of the lethal pool resulted in death within 8 days of three of three pig-tailed macaques. Comparison of the lethal virus, designated SIV/SMM(PBj14), with the parent virus, SIV/SMM-9 (the isolate with which macaque PBj was originally inoculated), showed that although the kinetics of replication in peripheral blood mononuclear cells (PBMC) from pig-tailed macaques and mangabey monkeys were similar, SIV/SMM(PBj14) replicated more efficiently than SIV/SMM-9 in human PBMC and also replicated in chimpanzee PBMC whereas SIV/SMM and other SIV isolates did not. In addition, the variant was shown to replicate efficiently in some established cell lines whereas replication of SIV/SMM-9 in cell lines could be demonstrated only occasionally. That parental SIV/SMM-9, but not SIV/SMM(PBj14), was neutralized by serum from macaque PBj suggests that the variant may have been generated by immune selection. Comparison of sequential virus isolates from macaque PBj for host range and the ability to be neutralized and of sequential serum samples for neutralization activity indicated that changes in biologic properties were detected in virus isolates and serum obtained at 6 months after infection and later. Normal macaque PBMC infected in vitro with SIV/SMM(PBj14), but not with SIV/SMM-9 or other virus pools from PBj, formed syncytia with Sup-T1 cells, whereas all isolates formed syncytia with MOLT-4 clone 8 cells. These data suggest that, relative to SIV/SMM-9, SIV/SMM(PBj14) acquired multiple mutations, at least one (or more) of which is in the gene coding for the envelope glycoprotein. Continued analysis of this series of SIV/SMM isolates with diverse properties may lead to the identification of specific regions of the viral genome that influence defined biologic properties. Furthermore, the availability of a strain of SIV that induces rapid onset of disease and death may facilitate screening of drugs for antiviral activity against lentiviruses.
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