Acquired immune deficiency syndrome (AIDS) has become a worldwide epidemic, so the development of vaccines and antiviral agents effective against the causative agent, human T-lymphotropic virus type III (HTLV-III), is vital. This work would be greatly simplified if a suitable animal model could be developed. Here we report the isolation of an HTLV-III-related retrovirus, STLV-III/Delta, from rhesus macaques (Macaca mulatta) with transmissible simian AIDS (SAIDS) and from asymptomatic sooty mangabeys (Cercocebus atys). SAIDS was initially diagnosed in several macaques previously inoculated with tissue homogenates of mangabey origin. Western blot analysis of both the mangabey and macaque sera demonstrated the presence of antibody cross-reactive primarily with the HTLV-III proteins p24 and p61. In a related experiment, analysis of these same sera revealed simian antibody to STLV-III/Delta proteins similar, but not identical, to those of HTLV-III with estimated relative molecular masses (Mrs) of 16,000 (16K), 26K, 35K, 45K, 60K and 110K. Infection of the mangabey, an African primate, with an HTLV-III-related virus may provide a clue to the origin of HTLV-III in humans. The apparent difference in susceptibility to SAIDS-like disease between infected macaques and mangabeys suggests that these species may respond differently to STLV-III infection.
A human epithelial cell line, FaDu, from a squamous cell carcinoma of the hypopharynx has been isolated and established from a patient from Calcutta, India. The cell line has a population doubling time of approximately 50 hours. Ultrastructural observation reveals the presence of bundles of tonofilaments in the cells and desmosomal regions distributed at the boundaries of adjacent cells. The cell line is susceptible to infection by some RNA‐ and DNA‐containing viruses.
A series of prodrugs of zidovudine (AZT) has been synthesized in an effort to enhance the uptake of the prodrugs by the HIV-1 infected cells and to increase the plasma half-life of AZT. The 5'-OH function of AZT was esterified with various acids in the presence of DCC and 4-(dimethylamino)pyridine (DMAP). The prodrug moieties included (a) morpholine and N-phenylpiperazine-1-acetic acid, (b) 1,4-dihydro-1-methyl-3-nicotinic acid, (c) retinoic acid, and (d) certain amino acids. The anti-HIV-1 activity of the esters was determined in peripheral blood lymphocytes. The IC50 for AZT in this system was 0.12 microM whereas for prodrugs it ranged from 0.05 to 0.2 microM. The prodrugs were generally less cytotoxic than AZT except the retinoic acid ester. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterases with t1/2 ranging from 10 to 240 min. Drug uptake studies in H9 cells with radiolabeled analogues demonstrated that the retinoic acid ester achieved approximately 4-fold higher intracellular concentration than [3H]AZT. However, 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester (5) was the most active agent of this series and had a higher therapeutic index than AZT.
A herpesvirus (RhEBV) was isolated from a lymphoblastoid cell line (LCL) that became established from a malignant lymphoma in a rhesus monkey. The predominant cell marker in the LCL was that of B lymphocytes. RhEBV-induced viral capsid (VCA) and nuclear antigens (NA) in the LCL were serologically related to similar antigens known to be induced by human Epstein-Barr virus (EBV). RhEBV was of nonhuman primate origin and was clearly differentiated from EBV in the anti-complement immunofluorescence reaction using human and non-human primate sera with antibodies to the NA induced by the respective viruses. While human sera reacted with NA induced by both EBV and RhEBV, monkey sera failed to recognize the NA induced by EBV. RhEBV-induced NA was present in nearly all the cells of a suspension prepared from the tumor tissue mass, but not in the monolayer fibroblasts derived from the tumor tissue or in the blood and lymph-node lymphocytes of clinically healthy animals. RhEBV induced in vitro transformation and establishment of LCLs from peripheral blood lymphocytes of normal rhesus and cynomolgus monkeys but not from those of 6 other non-human primate species tested. The LCLs, with predominant B-lymphocyte markers, established after treatment with RhEBV, all had evidence of the virus infection since nearly all cells in the culture expressed the virus-induced NA.
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