Carotid artery thickness is associated with chronic use of highly active antiretroviral therapy in patients infected with human immunodeficiency virus: A 3.0 Tesla magnetic resonance imaging study.

OBJECTIVES: While patients with HIV infection have an elevated stroke risk, ultrasound studies of carotid artery wall thickness have reported variable results. We hypothesized that subjects with HIV infection on chronic highly active antiretroviral therapy (HAART) would have increased carotid artery wall thickness by magnetic resonance imaging (MRI). METHODS: This cross-sectional study compared carotid artery wall thickness between 26 individuals infected with HIV on chronic HAART and 20 controls, without HIV infection but with similar cardiovascular risk factors, using 3.0-T noncontrast MRI. Inclusion criteria included male gender, age 35-55 years, and chronic HAART (≥ 3 years) among HIV-seropositive subjects; those with known cardiovascular disease or diabetes were excluded. RESULTS: Between subjects with HIV infection and controls, there were no differences in mean (±SD) age (47.8 ± 5.0 vs. 47.8 ± 4.7 years, respectively; P = 0.19) or cardiovascular risk factors (P > 0.05 for each). Mean (±SD) wall thickness was increased in those with HIV infection vs. controls for the left (0.88 ± 0.08 vs. 0.83 ± 0.08 mm, respectively; P = 0.03) and right (0.90 ± 0.10 vs. 0.85 ± 0.07 mm, respectively; P = 0.046) common carotid arteries. Among individuals with HIV infection, variables associated with increased mean carotid artery wall thickness included lipoaccumulation [+0.09 mm; 95% confidence interval (CI) 0.03-0.14 mm; P = 0.003], Framingham risk score ≥ 5% (+0.07 mm; 95% CI 0.01-0.12; P = 0.02 mm), and increased duration of protease inhibitor therapy (+0.03 mm per 5 years; 95% CI 0.01-0.06 mm; P = 0.02). CONCLUSIONS: Individuals with HIV infection on chronic HAART had increased carotid artery wall thickness as compared to similar controls. In subjects with HIV infection, the presence of lipoaccumulation and longer duration of protease inhibitor therapy were associated with greater wall thickness.

Randomized comparison of metabolic and renal effects of saquinavir/r or atazanavir/r plus tenofovir/emtricitabine in treatment-naïve HIV-1-infected patients.

OBJECTIVES: The aim of the study was to compare the effects on lipids, body composition and renal function of once-daily ritonavir-boosted saquinavir (SQV/r) or atazanavir (ATV/r) in combination with tenofovir/emtricitabine (TDF/FTC) over 48 weeks. METHODS: An investigator-initiated, randomized, open-label, multinational trial comparing SQV/r 2000/100 mg and ATV/r 300/100 mg once daily, both in combination with TDF/FTC, in 123 treatment-naïve HIV-1-infected adults was carried out. The primary endpoint was to demonstrate noninferiority of SQV/r compared with ATV/r with respect to the change in fasting cholesterol after 24 weeks. Secondary outcome measures were changes in metabolic abnormalities, body composition, renal function, and virological and immunological efficacy over 48 weeks. Patients who had used at least one dose of trial drug were included in the analysis. RESULTS: Data for 118 patients were analysed (57 patients on SQV/r and 61 on ATV/r). At week 24, changes in lipids were modest, without increases in triglycerides, including a significant rise in high-density lipoprotein (HDL) cholesterol and a nonsignificant decrease in the total:HDL cholesterol ratio in both arms with no significant difference between arms. Lipid changes at week 48 were similar to the changes observed up to week 24, with no significant change in the homeostasis model assessment (HOMA) index. Adipose tissue increased regardless of the regimen, particularly in the peripheral compartment and to a lesser extent in the central abdominal compartment, with an increase in adipose tissue reaching statistical significance in the ATV/r arm. A slight decline in the estimated glomerular filtration rate (eGFR) was observed in both arms during the first 24 weeks, with no progression thereafter. The immunological and virological responses were similar over the 48 weeks. CONCLUSIONS: Combined with TDF/FTC, both SQV/r 2000/100 mg and ATV/r 300/100 mg had comparable modest effects on lipids, had little effect on glucose metabolism, conserved adipose tissue, and similarly reduced eGFR. The virological efficacy was similar.

Common cell surface antigen associated with mammalian C-type RNA viruses. Cell membrane-bound gs antigen.

The indirect membrane immunofluorescence test and the absorption analysis of rabbit anti-FeLV, rabbit anti-FeLVp 30, and rabbit anti-MuLVp 30 antisera yielded the following conclusions. An antigen shared by mammalian (murine and feline) C-type RNA leukemia and sarcoma viruses was detected on the surface of cells infected or transformed by C-type viruses. The antigen was characterized as membrane-bound gs antigen bearing two determinants, membrane-bound gs-1, intraspecies-specific antigenic determinant, and membrane-bound gs-3, interspecies-specific antigenic determinant. Membrane-bound gs antigen was located on the cell surface, frequently near the site of virus budding but not on the envelope of murine C-type RNA virus.

Serum-mediated leukemia cell destruction in AKR mice.

AKR mice with spontaneous leukemia were infused with normal serum from a variety of species. Leukemia cell destruction was produced by serum from strains of mice possessing the full spectrum of complement components, but not by serum from strains with a genetically determined deficiency of C5. Serum from guinea pigs, horses, and humans also causes destruction of leukemia cells. The antileukemic factor in normal serum was heat labile (56 degrees C for 35 min) and could be inactivated by cobra venom factor (CVF). Tests of individual complement factors from guinea pig serum and from human serum suggest that C5 is the antileukemic complement component in normal serum. Evidence was obtained that complement also plays a role in the antileukemic effect of interferon and endotoxin.

Immunosurveillance of naturally occurring feline leukemia.

When compared to their housemates that subsequently developed leukemia, cats that remained healthy had five-to tenfold higher (geometric mean) humoral antibody titers to the feline oncornavirus-associated cell membrane antigen. This is compatible with the application of the immunosurveillance hypothesis to the natural development of leukemia in an outbred mammalian species.

Feline leukemia virus: occurrence of viral antigen in the tissues of cats with lymphosarcoma and other diseases.

Felinie leutkemia viruts antigen is demonstrable by immunodiffusion with rabbit precipitating antiserum to purified felinie leukemia virus. The felinie leukemia virus antigen was found in the tissues of 25 of 33 cats with lymphosarcoma and of 5 of 13 cats with infectious peritonitis. Its presence was correlated with the occurrence of felinie leukemia virus demonstrable by electron microscopy. The one clinically normal cat giving a positive test for feline leukemia virus antigen belonged to a household in which two cats had developed lymphosarcoma. With the exception of a dog with lymphosarcoma induced by feline leukemia virus, the antigent was absent from lymphosarcoma and nonlymphomatous tumors of other species (man, dog, cow, goat, or pig).

Search for evidence of feline leukemia virus infection in humans with leukemias, lymphomas, or soft tissue sarcomas.

Two-hundred and thirty-nine patients, including 66 with soft tissue sarcomas and 173 with hematologic cancers, were investigated for evidence of infection with feline leukemia virus (FeLV). Included in this group were 2 patients with acute lymphocytic leukemia who had lived in the same household with leukemic cats. None of the patients demonstrated measurable levels of neutralizing antibody to FeLV or had detectable FeLV antigens in peripheral blood normal leukocytes or leukemic cells. In a smaller number of patients, there was no evidence of antibody to FOCMA or of FOCMA on tumor cells in the bone marrow.

Shared interspecies antigenic reactivities among hamster and feline oncoviruses.

Group-reactive antisera against the major internal protein p30 of the hamster sarcoma virus (HaSV) showed interspecies reactivity in immunodiffusion even with sera of low titer against HaSV. Antisera were prepared by sc injection of virus into male New Zealand White rabbits. The cross-reactivity between interspecies antigens of feline and hamster RNA tumor viruses was stronger than between either virus with murine leukemia virus. Molecular hybridization data, obtained from nucleic acid hybridization between the viral RNA's and complementary DNA's of murine and feline oncovirus origin, were consistent with the immunologic results. THe implications of these observations were discussed.

Horizontal transmission of feline leukemia virus under experimental conditions.

Thirty-seven specific-pathogen-free (SPF) cats ranging from newborn to 1 year were inoculated with the Rickard strain of feline leukemia virus (FeLV). Each inoculated cat shared a cage with a control SPF cat for 40 weeks post inoculation. After 4-5 weeks, 20 of the inoculated cats became group-specific antigen (gsa)-positive; the other 17 remained gsa-negative but developed virus neutralizing and feline oncornavirus cell membrane-associated antigen antibody titers. Seventeen of the control cats in contact with the gsa-positive cats developed evidence of FeLV infection 4-18 weeks after virema was detected in their inoculated cage mates. Of the control cats in contact with inoculated cats that remained gsa-negative, none developed evidence of FeLV infection. Data indicated that the gsa-positive state in cats inoculated with FeLV correlated with the capacity for horizontal transmission of the virus.

Feline oncornavirus-associated cell membrane antigen. III. Antibody titers in cats from leukemia cluster households.

Serum samples from 182 healthy cats residing in environments known to have a natural exposure to feline leukemia virus (FeLV) were examined for the presence of antibody to the feline oncornavirus-associated cell membrane antigen. The number included 138 cats from leukemia-"cluster" households. Such cats previously showed greatly increased frequencies of FeLV infection, as determined by the virus group-specific antigen (gasa) in peripheral blood leukocytes and platelets. The geometric mean antibody titer for all 182 cats with known exposure to FeLV was 4.69, more than four times higher than the mean titer for healthy pet cats from the same geographic areas but with no known FeLV exposure. About 92 percent of the cats in exposure environments were positive for FeLV gsa or feline oncornavirus-associated cell membrane antigen (FOCMA) antibody, and gsa-positive cats had lower FOCMA antibody geometric mean titers than gsa-negative cats. In the exposure environments, no differences were seen for cats of different sexes, but a higher geometric mean antibody titer was observed for cats 5 years and over when compared to younger groups. These results prove that previous reports of increased incidences of leukemia in cluster households were not due to chance alone, but rather to increased infection rates of cats in the FeLV environment. Also, they suggest that horizontal transmission of FeLV is highly efficient under crowded conditions, and that most cats naturally exposed to virus elicit an active immune response.

Humoral immune responses of cats to feline leukemia virus: comparison of responses to the major structural protein p30 and to a virus-specific cell membrane antigen (FOCMA).

Radioimmunoprecipitation was used to test cat sera for ability to bind to the purified major internal protein p30 of feline leukemia viurs (FeLV), to the endogenous cat virus (RD-114), and to murine leukemia virus (MuLV). The data were compared with results of tests for antibody to the feline oncornavirus-associated cell membrane antigen FOCMA and for the presence of viremia. In contrast to the general lack of free antibody to FeLV p30 in a random sample of healthy cats, high levels of antibody to FeLV p30 and FOCMA were found in normal animals from high-leukemia-cluster households. Titers of greater than or equal to 200 for p30 and greater than or equal to 32 for FOCMA were found in nonviremic animals; a percentage of animals with high FOCMA titers and lower or no p30 binding activity were viremic. Animals with neoplasms were low or negative for FOCMA antibody and did not have high titers of free p30 antibody. The p30 binding activity could be divided into three main categories: high binding with FeLV p30 and much lower activity with RD-114 and MuLV p30's, as seen with hyperimmune sera; high binding with FeLV and RD-114 p30's and low activity with MuLV p30, possibly indicative of specific antibody to both of the aforementioned proteins; and low level binding to all three p30's.

Feline leukemia virus infection: age-related variation in response of cats to experimental infection.

Sixty-seven specific-pathogen-free cats of various ages (newborn, 2 wk, 1 mo, 2 mo, 4 mo, and 1 yr) were inoculated ip with either the Rickard (R) or the Kawakami-Theilen (KT) strain of feline leukemia virus (FeLV). Susceptibility to FeLV was judged by induction of a) FeLV group-specific antigens (gsa) in leukocytes, b) FeLV-related disease, c) antibody to feline oncornavirus-associated cell membrane antigen (FOCMA), and d) virus-neutralizing (VN) antibody. Susceptibility to FeLV-decreased with age. Persistent viremia and FeLV-related disease developed in 100% of cats inoculated as newborns, in 85% of cats inoculated at 2 weeks to 2 months of age, and in 15% of cats inoculated at 4 months or 1 year of age. Cats susceptible to FeLV leukemogenesis became persistently FeLV gsa-positive (viremic) at 4 weeks post inoculation and thereafter and produced little or no FOCMA or VN antibody. Cats that resisted leukemogenesis by FeLV all developed persistent FOCMA and VN titers and never became FeLV gsa-positive. The disease in inoculated cats was influenced by virus strain; FeLV-R induced predominantly thymic lymphosarcoma, whereas FeLV-KT caused fatal nonregenerative anemia without concurrent neoplasia.

Feline oncornavirus-associated cell membrane antigen. IV. Antibody titers in cats with naturally occurring leukemia, lymphoma, and other diseases.

Cats with naturally occurring leukemia and lymphoma had low or negative humoral antibody titers to the feline oncornavirus-associated cell membrane antigen (FOCMA). Geographic differences were seen in the relative frequencies of various forms of lymphoproliferative neoplasms. Lymphatic leukemia and thymic lymphoma were most common in Boston, whereas alimentary lymphoma was most frequent in Glasgow. No significant differences were found in geometric mean FOCMA antibody titers for the various forms of leukemia-lymphoma or for feline leukemia virus (FeLV)-positive as compared to FeLV-negative cats. Approximately 70% of 76 Boston cats with nonregenerative anemias were FeLV gs antigen (gsa) positive; this was similar to the percentage with leukemia-lymphoma from the same population that was positive. Fifty-five to 62% of the Boston cats with other infectious diseases, such as peritonitis and septicemia, were gsa positive. We postulate that this is due to a predisposition to infectious diseases by the immunosuppressive action of FeLV. Young cats from the Boston population that developed lymphoma, infectious peritonitis, and certain other diseases were more likely to be FeLV gsa positive than older cats with the same diseases.

Feline oncornavirus-associated cell membrane antigen. II. Antibody titers in healthy cats from household and laboratory colony environments.

Antibody titers to the feline oncornavirusassociated cell membrane antigen (FOCMA) were determined for 447 healthy cats from laboratory colony and household environments. Only 2.7 percent of 221 cats from colony environments were antibody positive as compared to 50.4 percent of 256 cats from household environments. Incidence of FOCMA antibody and geometric mean antibody titer for pet cats from New York City representing single cat apartment habitats were substantially lower than values for unscreened cats from the Boston, Glasgow, and Detroit suburban environments. Geometric mean antibody titer for young adults in the Boston population was significantly higher than titers for kittens or aged cats. This may be due to greater mobility resulting in increased exposure to other cats. In contrast to the high frequency of FOCMA antibody positivity in pet-cat populations, less than 2 percent of the same groups were positive for virus group-specific antigen in peripheral blood leukocytes and platelets. This was interpreted as an indication that many more cats became infected with feline leukemia virus under natural conditions that the number developing persistent virus infection and/or clinical leukemia.

Stimulation of erythropoietic differentiation in BALB/c mice infected with Rauscher leukemia virus.

The function of phenylhydrazine (PHZ) hemolysis in ameliorating the anemia induced in mice by a slow-acting strain of Rauscher leukemia virus (RLV-A) was described. After cessation of treatment with PHZ, mid-stage RLV-A-infected, anemic mice responded with massive reticulocytoses and a rebound in hematocrit above control levels. RLV-infected mice, subjected to PHZ-induced hemolysis or phlebotomy, produced high levels of plasma erythropoietin (Ep); this suggested that Ep mediated the PHZ-induced differentiation. In addition, administration of exogenous Ep induced a wave of erythroid maturation in RLV-infected anemic mice, which indicated that virus-infected erythroid precursors could still respond to the hormone governing normal differentiation.

Comparison of virus-positive and virus-negative cases of feline leukemia and lymphoma.

One hundred eighty-four cases of feline leukemia and lymphoma diagnosed in Boston from 1972 through 1976 were investigated. Fifty-eight % of these cases were lymphoma, and 42% were leukemia. Sixty-seven % of the cats had positive fluorescent antibody tests for circulating feline leukemia virus. The rest (33%) were virus negative. Clinically and epidemiologically, the virus-positive and virus-negative cases were remarkably similar except for their age at diagnosis. Virus-negative cats tended to be older (mean age at diagnosis, 4.9 years) as compared to virus-positive cats (3.5 years). For 22 cases of leukemia and lymphoma diagnosed after the age of 8 years, 15 were virus negative. The minimum mean induction period (time from first positive virus test to diagnosis of cancer) for 19 cats that were virus positive and healthy at their first test was 16.7 months (range, 2 to 41 months).

Natural feline leukemia virus infection and the immune response of cats of different ages.

Forty-two kittens and 28 adult cats were placed as tracers in leukemia cluster environments in contact with resident cats, 30% of which were persistently infected with feline leukemia virus (FeLV). After 7 months exposure, FeLV viremia had been detected in 71% of the tracer kittens, although only 55% of these remained persistently infected; in the same period, 11% of tracer adults became infected, but by 2 years the figure reached 43%. Mean latent periods before detection of viremia were 3.4 +/- 1.8 (S.D.) and 13.0 +/- 5.9 months for kittens and adults, respectively. First detection of FeLV infection was accompanied by a sharp although transient drop in peripheral white blood cell numbers, and infection onset triggered the humoral immune response which was comprised of separate antibodies with virus-neutralizing and tumor lysis activities. High titers of virus-neutralizing antibody appeared in transiently viremic cats immediately following elimination of viremia; this antibody was rarely detected in cats that remained persistently viremic. Lytic complement-dependent antibody to feline oncornavirus-associated cell membrane antigen appeared in most cats 1 to 2 weeks after FeLV infection was first detected, and subsequently high titers of this antibody remained in both transiently and persistently infected cats. If the rate of FeLV infection was summarized by using viremia and/or antibody appearance, then 95% of the kittens became infected within 1 year and 61% of the adults within 2 years. Adult cats are, therefore, susceptible to FeLV infection following long-term natural exposure, and their apparent resistance cannot be attributed to a protective humoral immune response that developed immediately after exposure commenced.

Immune response to leukemia virus and tumor-associated antigens in cats.

Cats represent an unusually valuable model for studying the role of the immune response to leukemia, lymphoma, and other mesodermal neoplasms. The agents that cause spontaneous feline leukemias, lymphomas, and fibrosarcomas, the feline leukemia and sarcoma viruses, are well characterized. A specific tumor cell membrane antigen, designated the feline oncornavirus-associated cell membrane antigen (FOCMA) has also been described. Feline leukemia and feline sarcoma viruses are antigenically indistinguishable, and FOCMA is common for both. Both laboratory-induced and spontaneous feline leukemias, lymphomas, and fibrosarcomas are available for study. A clear correlation has been shown between the resistance of cats to development of lethal tumors following inoculation of feline sarcoma virus and the presence of high humoral antibody titers to FOCMA. The geometric mean antibody titer to FOCMA for cats that resisted growth of fibrosarcomas was more than 20-fold higher than the mean for cats that succumbed to lethally progressing tumors. Cats with induced or spontaneous leukemia or lymphoma also have either no detectable FOCMA antibody or very low levels. Conversely, some cats resist development of leukemia or lymphoma following natural exposure to feline leukemia virus in leukemia cluster households, and these cats have high FOCMA antibody titers. These results support the concept of a natural immunosurveillance mechanism against leukemia or lymphoma development in an outbred mammalian species.

Feline lymphomas: immunological and cytochemical characterization.

The immunological and cytochemical phenotypes of five primary feline lymphomas and six feline lymphoma lines are reported. Thymic lymphomas induced by the Rickard strain of FeLV (FeLV-R) are of prothymocyte or (immature) cortical thymocyte origin, as these express terminal deoxynucleotidyl transferase, the guinea pig erythrocyte rosette receptor, Ia antigens, partial cortisone sensitivity, and nonspecific esterase. Lymphomas associated with other strains of FeLV form rosettes with guinea pig erythrocytes, frequently have Ia antigens and cytoplasmic nonspecific esterase, and probably originate from helper T-cells, monocyte/macrophages, or null cells. These data belie previous conclusions that FeLV leukemogenesis is restricted to mature T-cells; rather, the considerable heterogeneity in the surface and cytochemical phenotype of feline lymphomas probably reflects transformation of multipotent lymphoid or monocytoid precursors in the bone marrow by FeLV.

Biology of feline leukemia virus in the natural environment.

The feline leukemia virus (FeLV) was discovered in 1964 in a cluster of cats with lymphosarcoma. The observed clustering of cases of feline lymphosarcoma suggested that FeLV was an infectious agent for cats. The development of a simple immunofluorescent test for FeLV permitted a seroepidemiological study to be undertaken on the distribution of the virus in cats living in their natural environment. Over 2000 cats were tested, and the results showed conclusively that FeLV is an infectious agent for cats. This finding has now been independently confirmed using three different test procedures. After the infectious nature of FeLV was discovered, a simple FeLV test and removal program was devised to control the spread of the virus in the natural environment. The spread of FeLV was controlled in 45 households by removing the FeLV-infected cats, while in 25 households, where the infected cats were left in contact with the uninfected cats, 12% of the uninfected cats became infected. The ultimate control of FeLV awaits the development of an effective FeLV vaccine, which now seems feasible since we have already experimentally immunized some cats with attenuated FeLV. Although FeLV is infectious for cats there is no evidence that FeLV can infect humans.