Simian retrovirus vaccines: simian retrovirus and simian immunodeficiency lentivirus.
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AIDS Vaccines↗
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Molecular cloning and cell-specific growth characterization of polymorphic variants of type D serogroup 2 simian retroviruses.
Simian retroviruses (SRVs), the etiological agent of a spontaneous Simian acquired immunodeficiency syndrome, endemically infects large percentages of Asian macaques housed in biomedical research colonies and severely compromises the effective use of these species as a viable research animal. We recently described the molecular cloning of a serogroup 2 SRV, D2/RHE/OR, which causes mild immunosuppression in rhesus macaques. A restriction site variant, D2/RHE/OR/V1, has also been recovered from severely ill animals endemically infected with D2/RHE/OR. We now report the complete nucleotide sequences of D2/RHE/OR and D2/RHE/OR/V1. Both infectious molecular clones retain the genetic structure typical of type D SRVs (5' LTR-gag-prt-pol-env-3'LTR) and encode identically sized 8105-bp proviruses. D2/RHE/OR and D2/RHE/OR/V1 are 99.3% similar at the amino acid level, exhibiting only 17 residue differences, of which 10 are located in the envelope glycoproteins. The molecular clones and reciprocal chimeric viruses were used to assess the contribution of different genetic domains to virus infectivity in a T cell infection assay. These experiments indicate that D2/RHE/OR has a reduced ability to infect specific T cell lines, especially Hut-78 and MT-4 cells, and that the envelope gene is not the sole determinant of in vitro tropism.
Amino Acid Sequence↗
Langerhans cells in oral mucosa of rhesus monkeys before and after infection by simian retrovirus-1 and simian immunodeficiency virus.
To study the influence of experimental infection with simian retrovirus-1 and simian immunodeficiency virus on the number and distribution of Langerhans cells in oral mucosa of rhesus monkeys, 10 monkeys were intravenously inoculated with simian retrovirus-1, 7 with simian immunodeficiency virus, and 2 were mock-inoculated. Biopsies were taken from gingiva and cheek pouch before infection and at 1 (simian immunodeficiency virus group only), 4, and 7 months after infection. Langerhans cells were detected in frozen sections by immunohistochemistry with monoclonal antibodies Leu-6 and HLA-DR. The mean number of Langerhans cells per surface millimeter and square millimeter of epithelium was calculated under blind conditions. The results showed no statistically significant differences in the number or distribution of Langerhans cells in the three groups at the various time points of examination. Similarly, no differences were detected within any group over the observation period. Thus systemic infection of rhesus monkeys with either simian retrovirus-1 or simian immunodeficiency virus does not lead to a significant change in the number of Langerhans cells in oral mucosal epithelium.
Analysis of Variance↗
Mucosal epithelial cells and Langerhans cells are targets for infection by the immunosuppressive type D retrovirus simian AIDS retrovirus serotype 1.
Simian acquired immune deficiency syndrome (SAIDS) caused by the type D retrovirus SRV-1 results in opportunistic infections and a spectrum of oral lesions similar to those seen in humans with AIDS. To better understand the pathogenesis of these oral lesions we have retrospectively examined the oral mucosa from ten rhesus monkeys that died with SAIDS and prospectively examined the oral mucosa of ten additional animals inoculated with SRV-1 to determine at what time, and in what cells SRV-1 infection of the oral mucosa occurs. Using single and double label immunohistologic techniques, and electron microscopy we detected SRV-1 in clusters of oral epithelial cells and rare Langerhans cells as early as 1 month postinoculation.
Animals↗
Sustained increases in cerebrospinal fluid quinolinic acid concentrations in rhesus macaques (Macaca mulatta) naturally infected with simian retrovirus type-D.
Sustained increases in CSF concentrations of the excitotoxin quinolinic acid (QUIN) occur in patients with AIDS and have been implicated in the pathogenesis of the AIDS dementia complex. Macaques in captivity may also develop immunodeficiency syndromes caused by retrovirus infection, including simian retrovirus type-D. In the present study, CSF QUIN concentrations were moderately increased in retrovirus type-D-positive/antibody-negative macaques (163.8 +/- 35.1 nmol/l; P less than 0.0001, n = 21) but not virus-negative/antibody-positive macaques (27.4 +/- 9.4 nmol/l, n = 8) compared to uninfected control macaques (23.0 +/- 1.6 nmol/l; n = 22). CSF QUIN concentrations in virus-positive/antibody-negative macaques tended to remain elevated over a 4-20 month period. Post-mortem studies of 9 virus-positive/antibody-negative macaques and 6 virus-negative/antibody-positive macaques revealed inflammatory responses in the brains of 6 of 9 virus-positive/antibody negative macaques, including lymphocytic infiltrates of the choroid plexus in 3 macaques, glial nodules in 3 macaques and perivascular infiltrates in 1 macaque. These lesions were not extensive and no evidence of brain atrophy was observed. No lesions were observed in the 6 antibody-positive/virus-negative macaques. Small increases in plasma L-kynurenine in virus-positive/antibody-negative macaques are consistent with activation of indoleamine-2,3-dioxygenase, the first enzyme in the kynurenine pathway. We conclude that sustained moderate increases in CSF QUIN occur in viremic simian retrovirus type-D macaques. The increases in CSF QUIN may reflect inflammatory responses within the brain or synthesis of QUIN precursors in systemic tissues, their entry into brain and subsequent conversion to QUIN. The neuropathologic significance of these increases in CSF QUIN remains to be determined.
Animals↗
Spleen necrosis virus, an avian immunosuppressive retrovirus, shares a receptor with the type D simian retroviruses.
The reticuloendotheliosis viruses (REV) are a family of highly related retroviruses isolated from gallinaceous birds. On the basis of sequence comparison and overall genome organization, these viruses are more similar to the mammalian type C retroviruses than to the avian sarcoma/leukemia viruses. The envelope of a member of the REV family, spleen necrosis virus (SNV), is about 50% identical in amino acid sequence to the envelope of the type D simian retroviruses. Although SNV does not productively infect primate or murine cells, the receptor for SNV is present on a variety of human and murine cells. Moreover, interference assays show that the receptor for SNV is the same as the receptor for the type D simian retroviruses. We propose that adaptation of a mammalian type C virus to an avian host provided the REV progenitor.
Amino Acid Sequence↗
The simian retrovirus-1 constitutive transport element, unlike the HIV-1 RRE, uses factors required for cellular mRNA export.
BACKGROUND: A hallmark of retroviral gene expression is that unspliced retroviral genomic RNA is exported to the cytoplasm, whereas endogenous intron-containing cellular RNAs are usually retained in the nucleus. In complex retroviruses, such as human immunodeficiency virus-1 (HIV-1), nuclear export is accomplished by the interaction of a virally encoded protein, Rev, with a cis-acting RNA element, the Rev-responsive element (RRE). In type D retroviruses, such as the simian retrovirus type 1 (SRV-1), however, genomic RNA is exported by cellular factor(s) that interact with a conserved cis-acting RNA element, the constitutive transport element (CTE). RESULTS: We found that the CTE was exported in a specific and saturable fashion from Xenopus oocyte nuclei. When inserted into the intron of an adenovirus-derived pre-mRNA, the CTE did not affect splicing efficiency but promoted the nuclear export of the excised intron lariat that is normally retained within the nucleus. Export of CTE-containing RNAs to the cytoplasm was not affected by the heterogeneous nuclear ribonucleoprotein A1 or an excess of peptides corresponding to the Rev nuclear export signal. Microinjection of saturating amounts of CTE RNA did not affect tRNA export or Rev-mediated export but did inhibit mRNA export. CTE-mediated export was found to be dependent on Ran-mediated GTP hydrolysis. CONCLUSION: The Rev-RRE system and the CTE direct intron-containing RNAs to distinct export pathways. Although previous data have suggested that Rev uses the same export pathway as uracil-rich small nuclear RNAs and 5S ribosomal RNA, the CTE seems to interact with evolutionarily conserved factors that are essential for cellular mRNA export.
Animals↗
Viremia, antigenemia, and serum antibodies in rhesus macaques infected with simian retrovirus type 1 and their relationship to disease course.
The course of simian retrovirus type 1 (SRV-1) infection was studied in 14 experimentally inoculated juvenile rhesus monkeys. Viral transmembrane protein antigenemia and antibodies to whole virus were measured by enzyme linked immunosorbent assay and correlated with the clinical course of disease and virus isolation. Based on these parameters, animals with simian retrovirus type 1-induced disease were divided into three categories: monkeys dying within a few months of fulminating simian acquired immune deficiency syndrome in the face of a high level persistent antigenemia and viremia, and a nondetectable serum antibody response; monkeys that developed a milder form of simian acquired immune deficiency syndrome but remained alive in spite of a chronic low-grade antigenemia and viremia and only a transient initial antibody response; and monkeys that never became ill and that were either transiently or nontransiently viremic and antigenemic. This latter group developed high levels of serum antibodies. The outcome of simian retrovirus type 1-induced disease was similar to that described for feline leukemia virus infection of cats, another retroviral disease of animals. The disease course differed considerably, however, from that reported for retrovirus-induced human acquired immune deficiency syndrome.
Acquired Immunodeficiency Syndrome↗
Identification and analysis of the pseudoknot-containing gag-pro ribosomal frameshift signal of simian retrovirus-1.
The pro and pol genes of simian retrovirus-1 (SRV-1) are expressed as parts of a fusion protein generated by -1 ribosomal frameshifting. To investigate the requirements for frameshifting at the gag-pro overlap, we have inserted a stretch of 58 nucleotides containing the proposed frameshift signal into a plasmid that allows monitoring of translation in all three reading frames. In vitro translation of mRNAs derived from this plasmid indicated that the 58 nucleotides from the SRV-1 gag-pro overlap were sufficient to induce an efficient -1 shift in a heterologous context. Mutational analysis demonstrated that the slip site is formed at the heptanucleotide G GGA AAC. The frameshift efficiency of the wild type sequence in rabbit reticulocyte lysate was 23%. A second component of the frameshift signal is formed by a pseudoknot seven bases downstream of the slip site. The presence of this pseudoknot was confirmed by mutational analysis, employing complementary and compensatory base changes, and by probing the structure of short RNA transcripts containing the frameshift signal. Adding increasing amounts of an SRV-1 pseudoknot containing RNA transcript to a translation reaction programmed with an SRV-1 frameshift reporter mRNA had no effect on the frameshift efficiency, arguing against the role of a specific pseudoknot-recognising factor in the frameshifting process.
Base Sequence↗
Eradication of simian retrovirus type D from a colony of cynomolgus, rhesus, and stump-tailed macaques by using serial testing and removal.
The markedly compromised health of animals in a macaque colony and the problematic interpretation of data from two drug safety assessment studies prompted a review of the effect of simian retrovirus type D on the drug-development process at a Midwest pharmaceutical company. After reviewing relevant literature and consulting with an expert in simian retroviruses, we initiated a program of eradication. During a 16-month period, all cynomolgus (Macaca fascicularis), rhesus (Macaca mulatta), and stump-tailed (Macaca arctoides) macaques housed in the facility were evaluated as many as eight times for the presence of simian retrovirus type D by using serology, virus isolation, and/or polymerase chain reaction tests. All animals with positive test results were removed from the colony immediately. No test results indicative of simian retrovirus type D infection have occurred during the subsequent 2.5 years. We attribute the successful eradication and prevention of re-introduction of the virus to regular testing, purchasing animals from sources free of simian retrovirus type D, and assiduous application of procedures designed to prevent transmission between animals.
Animal Husbandry↗
A novel type D simian retrovirus naturally infecting the Indian Hanuman langur (Semnopithecus entellus).
As a simian species, the langurs are not known to harbor simian retroviruses, except for one report on a simian Type D endogenous retrovirus from the spectacled langur (Trachypithecus obscurus) from Malaysia. The present report describes for the first time natural infection of the common Hanuman langur (Semnopithecus entellus) from India by a novel simian retrovirus (SRV). The new SRV is phylogenetically related to but distinct from the three molecularly characterized serotypes, SRV 1-3, of the five known serotypes of SRVs, based on sequence analyses from the 3'orf and env regions of the viral genome. The novel SRV isolated from the Indian Hanuman langur is provisionally named SRV-6.
Amino Acid Sequence↗
Localization of the receptor gene for type D simian retroviruses on human chromosome 19.
Simian retrovirus (SRV) serotypes 1 to 5 are exogenous type D viruses causing immune suppression in macaque monkeys. These viruses exhibit receptor interference with each other, with two endogenous type D viruses of the langur (PO-1-Lu) and squirrel monkey, and with two type C retroviruses, feline endogenous virus (RD114/CCC) and baboon endogenous virus (BaEV), indicating that each utilizes the same cell surface receptor (M. A. Sommerfelt and R. A. Weiss, Virology 176:58-69, 1990). Vesicular stomatitis virus pseudotype particles bearing envelope glycoproteins of RD114, BaEV, and the seven SRV strains were employed to detect receptors expressed in human-rodent somatic cell hybrids segregating human chromosomes. The only human chromosome common to all the susceptible hybrids was chromosome 19. By using hybrids retaining different fragments of chromosome 19, a provisional subchromosomal localization of the receptor gene was made to 19q13.1-13.2. Antibodies previously reported to be specific to a BaEV receptor (L. Thiry, J. Cogniaux-Leclerc, R. Olislager, S. Sprecher-Goldberger, and P. Burkens, J. Virol. 48:697-708, 1983) did not block BaEV, RD114, or SRV pseudotypes or syncytia. Antibodies to known surface markers determined by genes mapped to chromosome 19 did not block virus-receptor interaction. The identity of the receptor remains to be determined.
Animals↗
Virus load and sequence variation in simian retrovirus type 2 infection.
The natural history of type D simian retrovirus (SRV) infection is poorly characterized in terms of viral load, antibody status, and sequence variation. To investigate this, blood samples were taken from a small cohort of mostly asymptomatic cynomolgus macaques (Macaca fascicularis), naturally infected with SRV type 2 (SRV-2), some of which were followed over an 8-month period with blood taken every 2 months. Provirus and RNA virus loads were obtained, the samples were screened for presence of antibodies to SRV-2 and neutralizing antibody titers to SRV-2 were assayed. env sequences were aligned to determine intra- and intermonkey variation over time. Virus loads varied greatly among cohort individuals but, conversely, remained steady for each macaque over the 8-month period, regardless of their initial levels. No significant sequence variation was found within an individual over time. No clear picture emerged from these results, which indicate that the variables of SRV-2 infection are complex, differ from those for lentivirus infection, and are not distinctly related to disease outcome.
Animals↗
Characterization of T- and B-cell epitopes of a simian retrovirus (SRV-2) envelope protein.
Synthetic envelope peptides of a simian retrovirus (SRV-2) were used to define both T- and B-cell epitopes of the envelope protein. The SRV-2 peptide 100-106 specifically blocks rhesus anti-SRV-2 neutralizing antibody activity, and a peptide 100-106 keyhole limpet hemocyanin conjugate induces a strong antipeptide antibody response. SRV-2 peptide 100-106 and 233-249 induces good T-cell proliferation of murine spleen cells immunized with the SRV-2 virus. Thus, SRV-2 envelope peptide 100-106 represents both a T- and B-cell epitope, and peptide 233-249 a T-cell epitope.
Amino Acid Sequence↗
Simultaneous detection of simian retrovirus type D serotypes 1, 2, and 3 by polymerase chain reaction.
Asymptomatic infection of macaques with macaques with simian retroviruses type D (SRV/D), the etiologic agents of one form of retrovirus-induced simian immunodeficiency disease, can confound experiments with the simian immunodeficiency virus (SIV), which also induces immunodeficiency disease in macaques. The SIV/macaque model is the preferred nonhuman primate model for AIDS-related research. Serological screening for SRV/D alone is insufficient because not all infected animals seroconvert, and virus isolation by cocultivation may require 4 to 6 weeks. We have established a DNA polymerase chain reaction (PCR) assay. One set of nested primers allows detection of SRV/D serotypes 1, 2, and 3 and distinguishes SRV-2 from the other two serotypes. The PCR assay is sensitive; a single proviral copy of SRV/D could be detected in 150,000 to 210,000 macaque peripheral blood mononuclear cells (PBMCs). When applied to a panel of virus isolation-positive macaque samples, the PCR assay was positive in 100% of the tests. No false-positive results were seen when known specific-pathogen-free (SPF) macaques were examined. We propose that macaques be screened with a combination of SRV/D serology and this DNA PCR assay prior to enrollment in experiments with SIV.
Animals↗
Quinolinic acid concentrations are increased in cerebrospinal fluid of Rhesus macaques (Macaca mulatta) naturally infected with simian retrovirus type-D.
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Animals↗
Simian retroviruses, poliovaccine, and origin of AIDS.
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Acquired Immunodeficiency Syndrome↗
Characterization of T cell epitopes on the envelope glycoprotein of simian retrovirus 1 and 2 (SRV-1 and SRV-2) in several mouse strains.
Various mouse strains were immunized with either SRV-1 or SRV-2 virus adsorbed on alum. Seven to 14 days later spleen cells were removed, and spleen cells were cultured with varying amounts of SRV-1 virus and SRV-2 virus, or varying amounts of selected SRV-1 and SRV-2 synthetic envelope peptides to determine their ability to initiate T cell proliferative responses. Our studies demonstrated that all mouse strains tested gave strong proliferative responses with SRV-2 virus. In contrast, SRV-1 virus induced T cell proliferative responses only in H-2k mouse strains. This apparent major histocompatibility complex (MHC)-restriction of SRV-1 virus-induced T cell proliferation correlates with the increased pathogenicity of SRV-1 virus in rhesus monkeys. The SRV envelope peptide 233-249 which is shared by both SRV-1 and SRV-2 virus initiates strong proliferative responses in both SRV-1 and SRV-2 virus immunized mice. The SRV-2 envelope peptide 96-102 initiates significant proliferative responses in SRV-2 immunized mice, and constitutes both a T and B cell epitope. The SRV-2 envelope peptide 127-152 has a 70% homology with the C-terminal region of SRV-1 peptide 142-167. The ability of SRV-2 peptide 127-152 to initiate T cell proliferation in SRV-1 virus immunized mice and the failure of the SRV-1 peptide 142-162 to initiate proliferation suggests that the region encompassing residues 160-167 must represent a T cell epitope in mice immunized with SRV-1 virus.
Amino Acid Sequence↗