Vaccination of macaques with SIV conserved envelope peptides suppressed infection and prevented disease progression and transmission.
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Adjuvants, Immunologic↗
Biomedical subjects
M G Lewis
Publications and source records attributed to M G Lewis.
Infection of rhesus and cynomolgus macaques with a rapidly fatal SIV (SIVSMM/PBj) isolate from sooty mangabeys.
A variant of simian immunodeficiency virus (SIVSMM/PBj), isolated from a chronically infected pig-tailed macaque has been shown in previous studies to produce acutely fatal disease uniformly in pig-tailed macaques and in some rhesus macaques. The present study extends investigation of SIVSMM/PBj pathogenesis in rhesus and cynomolgus monkeys. Cynomolgus and rhesus macaques were found to be uniformly susceptible to infection, but as previously reported, the rhesus were found to not be uniform in their response during the acute disease. Homogenized tissues from a rhesus that died acutely from SIVSMM/PBj were passaged to 6 rhesus monkeys in an attempt to increase lethality. Five of 6 rhesus monkeys receiving intravenous inoculation of either spleen (10(3) TCID50) or lymph node (10(5) TCID50) homogenate developed acute disease; 4 died (days 8-10), 1 recovered, and one rhesus remained asymptomatic. Three of 3 cynomolgus macaques and 4 of 4 pig-tailed macaques receiving the same inoculum died acutely within 9 days. Clinical disease in macaques that died was characterized by diffuse lymphadenopathy within 5 days of inoculation and severe diarrhea beginning 1 to 3 days before death. Anorexia, lymphopenia (< 1000 cells/mm3), and mild hypoalbuminemia preceded onset of diarrhea by 24 h. Viral p27 was detected in circulation by day 6 postinfection, with all animals dying acutely having detectable serum p27 and no detectable humoral response. Acute lethality was attributed to severe metabolic acidosis (pH < 7.20) which was observed 24-48 h prior to death in the pig-tailed and cynomolgus macaques. Immunohistochemistry revealed numerous SIV antigen-positive lymphocytes and macrophages in the lymph nodes, spleen, gut-associated lymphoid tissues and gastrointestinal lamina propria. Histopathologic lesions included marked to severe hyperplasia of the T-cell-dependent areas in lymphoid tissues and diffuse nonulcerative lymphohistiocytic gastroenteritis. Surviving rhesus developed strong humoral immune responses to the major SIV proteins.
Animals↗
Protection of macaques with a simian immunodeficiency virus envelope peptide vaccine based on conserved human immunodeficiency virus type 1 sequences.
This report describes the vaccination of rhesus macaques with peptides selected from regions of the simian immunodeficiency virus (SIV) envelope that are hydrophilic, immunoreactive, and highly homologous with corresponding conserved envelope sequences of the human immunodeficiency virus (HIV). The peptides, produced as beta-galactosidase fusion proteins, induced virus-neutralizing and peptide-specific antibodies. After challenge with virulent virus, controls became virus positive and developed gradually rising antibody titers to SIV over 63 weeks. Immunized macaques developed a postchallenge anamnestic response to SIVenv antigens within 3-6 weeks followed by a gradual, fluctuating decline in SIV antibody titers and partial or total suppression of detectable SIV. Virus suppression correlated with prechallenge neutralizing antibody titers. Although the average CD4+ cell count in the blood of immunized macaques remained constant, the control macaques exhibited a progressive decrease developing about week 55 after challenge. The conserved nature of the HIV and SIV peptides and the similar humoral immunoreactivity in the respective hosts suggest that homologous HIV peptides may be important components of a successful immunization strategy.
Amino Acid Sequence↗
Support and psychoeducation for parents of hospitalized mentally ill children.
Support and psychoeducational techniques were used in a group for parents of children hospitalized for psychiatric reasons. The parent's group model extends from more traditional, supportive, expressive group treatment to the use of didactic, concrete, cognitive components similar to the psychoeducational model used for families of mentally ill adults. Skills for dealing with limit setting, anger, and discipline were taught in a group climate that allowed for full expression of parental concerns. Guidelines for such a group program, including parent management techniques, are provided. The combination of modalities is the model's strength.
Adolescent↗
Variation in T-lymphocyte activation and susceptibility to SIVPBj-14-induced acute death in macaques.
In contrast to pig-tailed and cynomolgus macaques, which die in 6-10 days following infection with the SIV-PBj-14 isolate, only about 50% of rhesus succumbed to rapid disease. Using a CD45RA MAb that delineates memory (CD45RAlo), naive (CD45RAmed) and "activated" (CD45RAhi) T-cell subsets, it was seen that PBMC from pig-tailed and cynomolgus monkeys, unlike rhesus, have reduced CD4/CD8 ratios and a skewing of T cells towards CD45RAhi expression. Such preactivation of CD4+ cells could lead to enhanced viral replication and early death.
Acute Disease↗
Inhibition of phorbol ester-induced neutrophil chemiluminescence by FeLV.
Receptor-mediated activation is accompanied by phospholipid metabolism and by calcium fluctuation resulting in a chemiluminescence (CL) response in the neutrophil. This pathway involves activation of protein kinase C (PKC) and the NADPH oxidase. Artificial stimulants such as phorbol esters, specifically 12-O-tetradecanylphorbol-13-acetate (TPA), circumvent the receptor-mediated pathway and activate PKC resulting in a measurable CL response. Neutrophils from feline leukemia virus (FeLV) exposed cats were tested for their ability to generate a TPA-induced CL response. As compared to the non-FeLV-exposed specific-pathogen-free (SPF) control cat neutrophil CL responses, both viremic and nonviremic FeLV-exposed cats showed significant decreases in their CL responsiveness. Neither ultraviolet light-inactivated FeLV (UV-FeLV) nor protein components (FeLV-p15E and FeLV-p27) caused a significant decrease in the CL responses of the SPF cat neutrophils. The suppressed TPA-induced CL response from FeLV-infected cats may involve an intracellular mechanism not affected in vitro by exposure of the neutrophil to the virus or viral components.
Animals↗
Immunodeficiency in latent feline leukemia virus infections.
Challenge of naive experimental animals with a retroviral inoculum may result in one of two broad sequelae. The first is the establishment of an appropriate humoral and cellular immune response leading to a condition of immunity to subsequent infection with the retrovirus. Alternatively, the host may fail to develop a successful immune response, resulting in a chronic viremia associated with immunosuppression and ultimately death due to secondary pathogens. An alternate disease course is the establishment of a latent infection characterized by the presence of neutralizing antibody and strong cellular immune reactivity. Recent data from the feline leukemia virus (FeLV) system suggest that cats infected with this virus may develop immunosuppression in the form of persistent neutrophil dysfunction. The potential effect of this cellular dysfunction is the possible susceptibility of the host to the same opportunistic pathogens which are responsible for the increased mortality noted in chronic FeLV infections. These data demonstrate that persistent retroviremia is not essential for the establishment of immunosuppression. This overview presents data accumulated from the feline model of the human acquired immunodeficiency syndrome (AIDS) and discusses its relationship to human retroviral infections.
Acquired Immunodeficiency Syndrome↗
FeLV-induced immunosuppression through alterations in signal transduction: changes in intracellular free calcium levels.
Feline leukemia virus (FeLV) is a retrovirus with immunosuppressive properties. The mechanism(s) of immunosuppression is unknown. Calcium has been shown to be a second messenger in cellular activation and regulation. This study was designed to determine whether FeLV alters intracellular free calcium (IFC) levels in an FeLV-infected feline lymphoid cell line. Control cells and FeLV-infected cells were exposed to Concanavalin A, formyl-L-methionyl-L-leucyl-L-phenylalanine, and leukotriene B4. The basal IFC and post-stimulation IFC levels were recorded using Fura 2 AM and a luminescence spectrometer. Data collected indicate that FeLV-infected cells have a higher basal level of IFC and a reduced amount of increase in IFC after stimulation when compared to the control cells. The results would seem to indicate retrovirus-mediated interference occurring in the intracellular calcium signaling process.
Animals↗
FeLV-induced immunosuppression through alterations in signal transduction: down regulation of protein kinase C.
Activation of protein kinase C by a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), was shown to stimulate the respiratory burst in normal cat neutrophils. Neutrophils from feline leukemia virus (FeLV)-exposed viremic and nonviremic cats had significant suppression of their respiratory burst when stimulated with TPA. The addition of whole ultraviolet light-inactivated FeLV and FeLV proteins to normal cat neutrophils produced no significant suppression of the respiratory burst. These data suggest two possible mechanisms for suppression. The first is partially due to viral alterations of the neutrophil as seen in viremic cats, but, because exogenously applied FeLV or FeLV proteins had no effect on the respiratory burst, an additional mechanism is present. The second mechanism may be caused by a latent FeLV infection residing in nonviremic cat bone marrows which alters their immune system, resulting in immunosuppression.
Animals↗
Evidence that 8-methoxypsoralen (8-MOP) is a T-lymphocyte immunomodulatory agent.
This study was designed to characterize the effects of the anti-psoriatic compound 8-methoxypsoralen (8-MOP) on human lymphocyte function in vitro. Normal human peripheral blood mononuclear cells were stimulated with an optimal (1%) or a suboptimal (0.05%) concentration of phytohemagglutinin (PHA). At the optimal concentration of PHA, 8-MOP (140 microM) caused a delay in lymphocyte proliferation, interleukin-2 (IL-2) production/accumulation and IL-2 receptor expression. Addition of exogenous IL-2 to cultures stimulated with an optimal concentration of PHA did not overcome the delay of lymphocyte proliferation and IL-2 receptor expression. At the suboptimal concentration of PHA, 8-MOP (140 microM) caused a sustained inhibition of lymphocyte proliferation, IL-2 production/accumulation and IL-2 receptor expression. Addition of exogenous IL-2 under these conditions restored the magnitude of lymphocyte proliferation and IL-2 receptor expression. However, the responses displayed the delayed lymphocyte proliferation and IL-2 receptor expression typical of cells incubated with 8-MOP and an optimal concentration of PHA.
Adjuvants, Immunologic↗
Feline leukemia virus vaccine: new developments.
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Animals↗
Expression, release, and characterization of soluble human T-lymphotropic virus-I (HTLV-I) antigens from an infected cell line.
The Human T-lymphotropic virus type I (HTLV-I) infected cell line MT-2 was studied to obtain HTLV-I or related proteins for the purpose of producing an effective vaccine for HTLV-I infection. The cells were characterized as to HTLV-I antigen expression during the cell cycle and antigens released into the culture fluids. MT-2 cell grown in fetal calf supplemented media produced more HTLV-I related antigens during the G2/M phase of the cell cycle. To determine the conditions for maximal release and harvest of HTLV-I associated proteins, the MT-2 cells were grown in RPMI 1640 medium supplemented with serum-free medium. Cell- and virus-free supernatants were collected on day 4, lyophilized, and concentrated 50-fold. The proteins in these supernatants were characterized using SDS-PAGE and western blot using rabbit anti-HTLV-I sera and human adult T-cell leukemia sera. The western-blot analysis indicated that the supernatants obtained from the MT-2 cells grown in serum-free supplemented medium contained detectable amounts of proteins which reacted with human ATL and rabbit anti-HTLV-I sera. The molecular weights of these proteins observed are 68kd, 46kd, 28kd, 24kd, 19kd, and 15kd indicating that gag, env, and pX gene products are present.
Blotting, Western↗
Oral use of human alpha interferon in cats.
Low doses (0.5 or 5.0 U) of human alpha interferon (HuIFN alpha) given orally prevented the experimental development of fatal feline leukemia virus (FeLV)-related disease. Twenty-one FeLV-susceptible cats were inoculated with the Rickard strain of FeLV. Cats given oral HuIFN alpha survived significantly (p less than 0.001) longer than untreated FeLV-infected cats. Moreover, only 4 of 13 (30.8%) HuIFN alpha-treated cats developed clinical disease during the course of the study, whereas 100% of the untreated control cats developed fatal FeLV-related disease. Thus, in experimental retroviral disease, heterologous species HuIFN alpha provided significant clinical benefits.
Administration, Oral↗
Feline leukemia virus: current status of the feline induced immune depression and immunoprevention.
This is a review of the current knowledge of feline leukemia virus (FeLV) associated with immune depression observed in cats. It will focus on the clinical and experimental observations associated with feline retroviral infection and presence in vivo and in vitro. We will briefly describe retroviral-associated acquired immune deficiency syndrome associated with FeLV infection in the cat and specific cellular pathology associated with FeLV latency. In addition, we will focus on the action of FeLV-p15E in vitro and describe possible mechanisms of the FeLV-associated immunosuppression observed both in vivo and in vitro. Lastly, we will evaluate the current status of immunoprevention of FeLV. We will not attempt an in-depth analysis of the current literature; our focus is to review current findings as they relate to feline AIDS and immunotherapy.
Acquired Immunodeficiency Syndrome↗
Suppression of in vitro neutrophil function by feline leukaemia virus (FeLV) and purified FeLV-p15E.
Feline neutrophils (PMN) were isolated and exposed to ultraviolet light-inactivated feline leukaemia virus (UV-FeLV) and purified envelope component p15E (FeLV-p15E). Functional capacity of exposed PMN was measured in vitro utilizing the chemiluminescence (CL) response. PMN exposed to UV-FeLV demonstrated depressed CL responses to Ca2+-ionophore A23187 and latex particles. However, FeLV-p15E produced significant suppression in the CL response to A23187 but failed to produce significant alterations in response to latex particles. The data indicate that FeLV-p15E may, in part, be responsible for increased morbidity and mortality among FeLV-infected cats through suppression of the PMN population.
Animals↗
Saliva as a source of feline leukemia virus antigen for diagnosis of disease.
An enzyme-linked immunosorbent assay (ELISA) for detection of feline leukemia virus (FeLV) p27 in saliva was tested for its accuracy and sensitivity in diagnosing FeLV infections. Saliva and serum samples from 564 clinical cases were tested with a 99.2% specificity. The overall accuracy of the saliva ELISA reactive to the serum ELISA was 97.9%. Experimentally, the ELISA saliva was the least sensitive in diagnosing early FeLV infections. However, the overall accuracy, ease of use, and simplicity of the test support its use as a screening procedure in clinical practice.
Animals↗
Identification of calmodulin activity in purified retroviruses.
Several viruses have been shown to require calcium for their function, and to bind calcium at specific sites. However, the nature of the calcium binding molecule on viruses has not been established. One possibility is the ubiquitous calcium-binding protein calmodulin. Our studies were designed to determine whether feline leukemia virus contained calmodulin. Accordingly, we tested purified feline leukemia virus for the presence of calmodulin-like activity. The virus, like authentic calmodulin, activated cyclic AMP phosphodiesterase. The ability of the virus to activate the enzyme was blocked in the presence of the known calmodulin inhibitors trifluoperazine and W-7. This indirect evidence for the presence of calmodulin was confirmed by radioimmunoassay. Several other retroviruses were also tested using radioimmunoassay and found to contain calmodulin. Our results indicate that the calcium binding site in retroviruses may be calmodulin.
3',5'-Cyclic-AMP Phosphodiesterases↗
Feline leukemia vaccine: efficacy, contents and probable mechanism.
An effective subunit vaccine against feline leukemia virus infection and related diseases has been developed. The source of the vaccine immunogen is feline retrovirus persistently infected cells that continuously synthesize and shed virus polypeptides. Western blot analysis identifies FeLV-gp70, p27, p15, p12, and p10 in the subunit vaccine preparation. Cats immunized with the vaccine developed antibodies to a 70,000 MW protein of the vaccine that seems to be distinct from, but related to the FeLV-gp70 polypeptide.
Animals↗