Oral transmission of primate lentiviruses.
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Oral transmission of human immunodeficiency virus type 1 (HIV-1) is well documented in children who become infected postnatally through breast milk. In contrast, epidemiologic surveys have yielded conflicting data regarding oral HIV-1 transmission among adults, even though case reports have described seroconversion and the development of AIDS in adults whose only risk was oral-genital contact. To study oral virus transmission in primate models, we exposed rhesus macaques of various ages to cell-free simian immunodeficiency virus (SIV), including uncloned and molecularly cloned viruses. In neonates, viremia and AIDS developed after nontraumatic oral exposure to several SIV strains. Furthermore, chimeric simian human immunodeficiency viruses containing the HIV-1 envelope can also cross intact upper gastrointestinal mucosal surfaces in neonates. In adult macaques, infection and AIDS have resulted from well-controlled, nontraumatic, experimental oral exposure to different strains of SIV. These findings have implications for the risks of HIV-1 transmission during oral-genital contact. (+info)
T cell-tropic simian immunodeficiency virus (SIV) and simian-human immunodeficiency viruses are readily transmitted by vaginal inoculation of rhesus macaques, and Langerhans' cells of the female genital tract are infected with SIV.
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Intravaginal inoculation with T cell-tropic molecular clones of simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) or some dual-tropic strains of SIV or SHIV produced systemic infection in rhesus macaques. Vaginal inoculation with other dual-tropic molecular clones of SIV or SHIV did not infect rhesus macaques even after multiple inoculations. While in vitro measures of macrophage tropism do not predict which primate lentiviruses will produce systemic infection after intravaginal inoculation, the level to which a virus replicates in vivo after intravenous inoculation does predict the outcome of intravaginal inoculation. Another series of studies, using combined in situ hybridization and immunolabeling to simultaneously detect SIV RNA and identify the immunophenotype of infected cells, demonstrated that a large proportion (approximately 40% in some animals) of the SIV-infected cells in the vagina and cervix were Langerhans' cells. This is the first in vivo demonstration that Langerhans' cells in the genital tract are infected with SIV and that dendritic cells are significant reservoirs for lentiviruses. (+info)
Mucosal Th1- versus Th2-type responses for antibody- or cell-mediated immunity to simian immunodeficiency virus in rhesus macaques.
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Simian immunodeficiency virus (SIV)-specific B cell responses and the Th1- or Th2-type profiles of cytokine expression were determined for rhesus macaques immunized with SIV antigens via the iliac lymph nodes (by use of a targeted lymph node [TLN] procedure) or orally with SIV p55gag plus cholera toxin (CT) as a mucosal adjuvant. Analysis of CD4+ T cells purified from SIV-stimulated peripheral blood mononuclear cells of immunized macaques revealed that Th2 cytokine production gradually increased after the second and third TLN immunization. Analysis of SIV-specific B cell responses revealed that peak SIV-specific IgA B cell responses followed the third TLN immunization and occurred during peak Th2-type T cell responses. Oral immunization of macaques with p55gag plus CT induced interferon-gamma-secreting Th1-type and select Th2-type cytokine-producing CD4+ T helper cells, which most likely accounted for the induction of p55-specific systemic IgG and mucosal IgA responses. (+info)
Immunohistochemical localization of receptors for progesterone and oestradiol-17 beta in the implantation site of the rhesus monkey.
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The aim of the present study was to examine the cellular basis of the involvement of oestradiol and progesterone in blastocyst implantation in the primate. To this end, the cellular distribution of receptors for oestradiol (ER) and progesterone (PR) in fetal trophoblast cells and in endometrial compartments of timed lacunar (pre-villous) and villous stages of placentation in primary implantation sites collected on days 13-22 of gestation were investigated in rhesus monkeys. Both in pre-villous stage tissue and in villous stage tissue, cytotrophoblast cells and syncytiotrophoblast cells and other trophoblast derived cells were PR positive, while they were generally ER negative. Maternal endometrial cells were ER negative, while epithelial cells, stromal cells and vascular endothelial cells in maternal endometrium showed heterogeneous staining patterns for PR depending on their relative location; these patterns, however, correlated well with glandular hyperplasia and differentiation, stromal-decidual transformation and vascular response seen during blastocyst implantation. (+info)
Metabolism and disposition of 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) in rhesus monkeys.
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Metabolism and disposition of the tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent rodent lung carcinogen, were studied in rhesus monkeys. In three males receiving a single i.v. dose of [5-3H]NNK (0.72 mCi; 4.6-9.8 microg/kg), urine was collected for 10 days. Within the first 24 h, 86.0 +/- 0.7% of the dose was excreted. NNK-derived radioactivity was still detectable in urine 10 days after dosing (total excretion, 92.7 +/- 0.7%). Decay of urinary radioactivity was biexponential with half-lives of 1.7 and 42 h. Metabolite patterns in urine from the first 6 h closely resembled those reported previously for patas monkeys; end products of metabolic NNK activation represented more than 50% of total radioactivity. At later time points, the pattern shifted in favor of NNK detoxification products (60-70% of total radioactivity in urine), mainly 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its O-glucuronide conjugates. One female rhesus monkey received a single i.v. dose of [5-3H]NNK (1.72 mCi; 28.4 microg/kg) under isoflurane anesthesia; biliary excretion over 6 h (0.6% of the dose) was 10 times less than predicted by our previously reported rat model. No preferential excretion of NNAL glucuronide was observed in monkey bile. Collectively, these results suggest that the rhesus monkey could be a useful model for NNK metabolism and disposition in humans. (+info)
Latrunculin-A increases outflow facility in the monkey.
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PURPOSE: To determine the effect of Latrunculin (LAT)-A, a macrolide that binds to G-actin, which leads to the disassembly of actin filaments, on shape, junctions, and the cytoskeleton of cultured bovine aortic endothelial cells (BAECs) and on outflow facility in living monkeys. METHODS: Latrunculin-A dose-time-response relationships in BAECs were determined by immunofluorescence and phase contrast light microscopy, facility by two-level constant pressure anterior chamber perfusion. RESULTS: In BAECs, LAT-A caused dose- and incubation time- dependent destruction of actin bundles, cell separation, and cell loss. Cell-cell adhesions were more sensitive than focal contacts. Recovery was also dose- and time-dependent. In monkeys, exchange intracameral infusion and topical application of LAT-A induced dose- and time-dependent several-fold facility increases. The facility increase was completely reversed within several hours after drug removal. However, for at least 24 hours after a single topical LAT-A dose, perfusion with drug-free solution caused an accelerated increase in facility beyond that attributed to normal resistance washout. CONCLUSIONS: Pharmacological disorganization of the actin cytoskeleton in the trabecular meshwork by specific actin inhibitors like LAT-A may be a useful antiglaucoma strategy. (+info)
Pharmacokinetics of beta-L-2',3'-dideoxy-5-fluorocytidine in rhesus monkeys.
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beta-L-2',3'-Dideoxy-5-fluorocytidine (beta-L-FddC), a novel cytidine analog with an unnatural beta-L sugar configuration, has been demonstrated by our group and others to exhibit highly selective in vitro activity against human immunodeficiency virus types 1 and 2 and hepatitis B virus. This encouraging in vitro antiviral activity prompted us to assess its pharmacokinetics in rhesus monkeys. Three monkeys were administered an intravenous dose of [3H] beta-L-FddC at 5 mg/kg of body weight. Following a 3-month washout period, an equivalent oral dose was administered. Plasma and urine samples were collected at various times for up to 24 h after dosing, and drug levels were quantitated by high-pressure liquid chromatography. Pharmacokinetic parameters were obtained on the basis of a two-compartment open model with a first-order elimination from the central compartment. After intravenous administration, the mean peak concentration in plasma (Cmax) was 29.8 +/- 10.5 microM. Total clearance, steady-state volume of distribution, terminal-phase plasma half-life (t1/2 beta), and mean residence time were 0.7 +/- 0.1 liters/h/kg, 1.3 +/- 0.1 liters/kg, 1.8 +/- 0.2 h, and 1.9 +/- 0.2 h, respectively. Approximately 47% +/- 16% of the intravenously administered radioactivity was recovered in the urine as the unchanged drug with no apparent metabolites. beta-L-FddC exhibited a Cmax of 3.2 microM after oral administration, with a time to peak drug concentration of approximately 1.5 h and a t1/2 of 2.2 h. One monkey in the oral administration arm of the study had a significant delay in the absorption of the aqueous administered dose. The absolute bioavailability of orally administered beta-L-FddC ranged from 56 to 66%. (+info)
Effect of 3-hydroxyphthaloyl-beta-lactoglobulin on vaginal transmission of simian immunodeficiency virus in rhesus monkeys.
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Heterosexual transmission of human immunodeficiency virus type 1 (HIV-1) is the major cause of the ongoing AIDS epidemic. Application of chemical barrier methods is expected to contribute to the worldwide control of this epidemic. Bovine beta-lactoglobulin modified by 3-hydroxyphthalic anhydride (3-hydroxyphthalovyl-beta-lactoglobulin [3HP-beta-LG]) was shown to inhibit HIV-1, HIV-2, simian immunodeficiency virus (SIV), herpes simplex virus type 1 and 2, and Chlamydia trachomatis infection in vitro. Here, we show that 3HP-beta-LG not formulated into any vehicle protected three of six rhesus monkeys against vaginal infection by SIV. Incorporation of the compound into an appropriate vehicle is expected to increase the degree of protection. 3HP-beta-LG may be effective as a vaginal inhibitor of HIV-1 infection in humans. (+info)