Simian retrovirus D serogroup 1 has a broad cellular tropism for lymphoid and nonlymphoid cells.

Simian acquired immunodeficiency syndrome is a fatal immunosuppressive disease caused by type D retroviruses such as simian acquired immunodeficiency syndrome retrovirus type 1 (SRV-1). The disease is characterized by generalized lymphadenopathy, opportunistic infections, and lymphoid depletion with defects in both humoral and cell-mediated immunity. To understand how SRV-1 infection relates to the immune defect, we studied in vivo-infected lymphocytes from SRV-1-positive macaques with and without clinical signs of immunosuppressive disease. B and T helper/inducer and T suppressor/cytotoxic lymphocytes were purified by panning or by flow cytometry. Neutrophils were purified by dextran sedimentation, and platelets were purified by low-speed centrifugation. In vitro infection studies were also done with HUT78, H9, K562, rhesus lung fibroblast, rhesus monkey kidney, and bat lung cells. SRV-1 in lymphocytes or culture supernatants was detected by the induction of syncytia in cocultivated Raji cells and was confirmed by immunofluorescence, electron microscopy, or reverse transcriptase assay. We found that B and T helper/inducer lymphocytes were infected in all animals tested. The number of infected T suppressor/cytotoxic cells was generally lower than that of the other cell subsets, and not all animals in this subset had SRV-1 infections. All other cells exposed in vitro to SRV-1, except bat lung cells, were able to be infected. These findings show that SRV-1 has a broad cell tropism for lymphoid and nonlymphoid cell types.

Prevention of simian acquired immune deficiency syndrome with a formalin-inactivated type D retrovirus vaccine.

Experimental induction of simian acquired immune deficiency syndrome (SAIDS) by inoculation of juvenile rhesus monkeys with a type D retrovirus was prevented by immunization with Formalin-killed whole SAIDS retrovirus serotype 1 containing the adjuvant threonyl muramyl-dipeptide. All six immunized animals developed neutralizing antibody after three injections, while six age-matched cagemates receiving adjuvant alone were antibody free. All 12 monkeys were challenged intravenously with a potentially lethal dose of SAIDS retrovirus serotype 1. The six immunized animals failed to develop persistent viremia and remained clinically normal 8 months postchallenge. In contrast, five of six nonvaccinates developed persistent viremia, four of six developed clinical SAIDS, and two of six died with SAIDS at 10 weeks and 8 months postchallenge, respectively. These results show that prevention of a common spontaneous retrovirus-induced immunosuppressive disease in macaques is now possible by vaccination.

Pathogenesis of simian AIDS in rhesus macaques inoculated with the SRV-1 strain of type D retrovirus.

Type D retrovirus was isolated from rhesus macaques with simian acquired immunodeficiency syndrome (SAIDS) and transmitted to healthy rhesus macaques with tissue culture medium containing the virus. The clinical, immunologic, and lymph node morphologic changes were observed in 9 rhesus macaques for 52 weeks after inoculation. A spectrum of clinical signs developed including early death, persistent SAIDS, and apparent remission. Animals that died or developed persistent SAIDS had characteristic lymphoid depletion, persistently depressed peripheral blood mononuclear cell (PBMC) mitogenic response, and decreased serum immunoglobulins. The SAIDS retrovirus (SRV) was recovered from PBMC of 8 of the animals after inoculation. Virus could not be recovered from PBMC of one animal in remission, but this animal developed serum-neutralizing antibodies to SRV after inoculation. Seven of the animals seroconverted to SRV after inoculation, all 9 were seronegative for human T-lymphotropic virus-III, and 5 animals tested were seronegative to human T-lymphotropic virus-I. These findings support the etiologic role of the type D retrovirus in SAIDS and further define the pathogenesis of this disease.

Isolation of a new serotype of simian acquired immune deficiency syndrome type D retrovirus from Celebes black macaques (Macaca nigra) with immune deficiency and retroperitoneal fibromatosis.

A new serotype of simian acquired immune deficiency syndrome (SAIDS) retrovirus (type 2) belonging to the D genus of retroviruses is associated with a SAIDS occurring spontaneously in a colony of Celebes macaques (Macaca nigra) and rhesus macaques (Macaca mulatta) at the Oregon Regional Primate Research Center. This syndrome resembles SAIDS in M. mulatta at the California Primate Research Center, which is associated with a similar type D retrovirus (type 1). However, at the Oregon Center, SAIDS is distinguished by the occurrence of retroperitoneal fibromatosis in some of the affected monkeys. Type 2 virus was isolated from seven of seven macaques with SAIDS, retroperitoneal fibromatosis, or both and from one of six healthy macaques. The new strain is closely related to SAIDS retrovirus type 1 and Mason-Pfizer monkey virus but can be distinguished by competitive radioimmunoassay for minor core (p10) antigen and by genomic restriction endonuclease cleavage patterns. Neutralization tests indicate that type 1 and type 2 SAIDS retroviruses are distinct serotypes. Therefore, separate vaccines may be necessary to control these infections in colonies of captive macaques.

The effect of ketamine on endotoxin-induced lung injury.

We investigated the effects of ketamine HCl on endotoxin-induced pulmonary injury in 20 chronically instrumented sheep with lung lymph fistulas. The caudal mediastinal lymph node was cannulated in 20 ewes (45-55 kg). The catheter was externalized and the lymph allowed to drain freely. Pulmonary injury was induced by an intravenous infusion of Escherichia coli endotoxin (1.0-1.5 micrograms/kg body wt) over a 5-min period in 11 animals. The injury was characterized by an increase in pulmonary arterial pressure, pulmonary arterial wedge pressure, and lung lymph flow. There was no change in mean systemic arterial pressure. These changes were significantly attenuated by intravenous administration of ketamine HCl (5 mg/kg) following endotoxin injury in 9 other animals. When ketamine was given, the pulmonary arterial pressure decreased 32%, lung lymph flow decreased 27%, and systemic blood pressure increased 22%. Potential mechanisms for the hemodynamic effects of ketamine HCl in sepsis are discussed with particular reference to the pulmonary microvasculature.

Pulmonary microvascular response to prostacyclin (PGI2) infusion in unanesthetized sheep.

We studied the effect of prostacyclin (PGI2) infusion and cessation of infusion on the pulmonary microcirculation. We used lung lymph flow (QL) and the lymph to plasma protein ratio as sensitive indices of net fluid (QF) and protein flux (CP). After a 4-h base line period, we infused PGI2 (0.2 micrograms . kg(-1).min(-1) into eight unanesthetized sheep for 2 h. We monitored vascular pressures and lymph during infusion and for another 18 h after PGI2. During infusion, QL and cardiac output increased by 75 and 50%, respectively, over base line, whereas the lymph-to-plasma ratio (L/P) remained constant for both albumin and globulin. This resulted in a significant increase in both fluid and protein flux. Pulmonary vascular pressures remained unchanged, whereas mean aortic pressure decreased. The increase in QF and CP was felt to be due to an increase in the surface area of fluid exchange vessels rather than increased permeability. After infusion, cardiac output rapidly returned to base line, whereas mean QL remained increased by 70% over base line for 2-8 h. Mean L/P decreased from 0.65 to 0.53. Pulmonary arterial pressure and pulmonary vascular resistance increased. The increase in QL and decrease in L/P indicate a rebound increase in pulmonary microvascular pressure in the postperfusion period.

Prostaglandin infusion and endotoxin-induced lung injury.

The use of prostaglandins is currently undergoing clinical trials in respiratory failure accompanying sepsis. The effect of prostaglandin E1 (PGE1) and prostacyclin (PGI2) infusion on endotoxin-induced lung injury, with attention to interstitial fluid flux (QL), pulmonary vascular pressure (Ppa), leukocytes, platelets, and release of the lysosomal enzyme beta-glucuronidase, was investigated. A chronic lung lymph fistula model in sheep was used. Seven sheep alternately received Escherichia coli endotoxin and endotoxin plus PGE at a dosage of 1 microgram/kg/min. Six sheep received PGI2 (0.2 microgram/kg/min) instead of PGE1. Both PGE1 and PGI2 decreased the pulmonary hypertension and the interstitial edema produced by endotoxin primarily through their vasodilatory properties. Prostacyclin seemed to have an additional membrane-stabilizing effect. A rebound increase in QL, Ppa, and platelets occurred when PGE1 or PGI2 infusion was discontinued.

Pulmonary microvascular injury from lipoxygenase infusion: comparison with endotoxemia.

We compared the response of the pulmonary microcirculation to a 5-hr infusion of soybean lipoxygenase with that seen after endotoxin. We monitored microvascular integrity using lung lymph flow QL and lymph/plasma (L/P) protein ratio in unanesthetized sheep. We noted a twofold to threefold increase in QL and a slight decrease in L/P ratio beginning about 1 hr after onset of the lipoxygenase infusion. Leukocyte count decreased significantly and lymph lysosomal enzyme activity increased. Pulmonary artery pressure initially increased from 16 to 31 mm Hg, then decreased to 25 mm Hg during continued infusion. Platelet count remained constant. Parameters returned to baseline several hours after infusion. This pulmonary vascular pressure and lymph flow response was very similar to that seen in the increased permeability phase of endotoxin. A decrease on the L/P ratio and a constant rather than a decreased platelet count were findings different from those seen after endotoxin.