Sequence analysis and acute pathogenicity of molecularly cloned SIVSMM-PBj14

Abstract

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.

Molecularly Cloned SHIV-1157ipd3N4: a Highly Replication- Competent, Mucosally Transmissible R5 Simian-Human Immunodeficiency Virus Encoding HIV Clade Cenv

“…For instance, SIVmac239, the backbone normally used for the construction of SHIV chimeras, has one NF-B binding element. However, duplication of NF-B binding sites in monkey-passaged SIVs can result in acutely lethal variants such as SIVpbj14 (17) or pathogenic progeny that had evolved from live attenuated SIVmac239⌬3 (1). In the latter case, progeny virus containing two NF-B sites had replaced the original virus, implying better in vivo replicative capacity of virus that had emerged late in the course of the infection (1).…”

Heterogeneity in Neutralization Sensitivities of Viruses Comprising the Simian Immunodeficiency Virus SIVsmE660 Isolate and Vaccine Challenge Stock

“…Regions that could not be unambiguously aligned were removed from the analysis. Sequence data sets include published SIVsmE660 and SIVmac251 sequences (32,52,53), published SIVsmm sequences (5,(45)(46)(47)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64), and HIV-1 group M sequences from the Los Alamos National Laboratories Subtype Reference set (47,65,66).…”

Early replication block of human immunodeficiency virus type 1 in monkey cells

“…The species tropism of HIV-1 is narrower than that of viruses of the HIV-2 subgroup (HIV-2, SIV~A c and SIVMN E of the macaque monkey and SIVsM of the sooty mangabey, Cercocebus atys). Only higher primates [humans, chimpanzees (Pan troglodytes), gibbons (Hylobates lar)] and pig-tailed macaques (M. nemestrina) are susceptible to HIV-1 infection in vivo (Agy et al, 1992;Alter et al, 1984;Fultz et al, 1986;Gajdusek et al, 1985;Lusso et al, 1988;Nara et al, 1987), whereas various primates [humans, rhesus monkeys (Macaca mulatta), cynomolgus monkeys (M. fascicularis), pig-tailed monkeys, and sooty mangabeys] are productively infected with viruses of the HIV-2 subgroup (Benveniste et al, 1988;Daniel et al, 1985;Dewhurst et al, 1990;Franchini et al, 1990;Letvin et al, 1985;Naidu et al, 1988). In cultured peripheral blood mononuclear cells (PBMC), growth of HIV-1 is similarly restricted .…”