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Biomedical subjects

G V Quinnan

Publications and source records attributed to G V Quinnan.

At least 19 recordsLinked to original sources
PubMed1998

Evolution of neutralizing antibody response against HIV type 1 virions and pseudovirions in multicenter AIDS cohort study participants.

Changes in neutralizing antibody (NA) titers in stored sera collected over 5 years from 10 participants in the Multicenter AIDS Cohort Study (MACS) were evaluated. The participants were HIV-1 infected on enrollment in the MACS, and remained AIDS free during the 5-year study interval. Seven viruses derived from molecular clones were used in NA assays; five of the viruses were T tropic (NL4-3, ALA1, NY5, SF2, and Z2Z6) and two were M tropic [AD8 and NL(SF162)]. In addition, pseudoviruses (PVs) were constructed that expressed envelope genes from NL4-3, ALA1, AD8, and SF162 and from primary viruses from two MACS participants (PV-9 and PV-10). There was significant correlation between NA titers obtained in four of five virus/PV comparisons, while the SF162 PV was more sensitive to NA than the corresponding virus. Comparable changes in NA titers were detected using viruses and PVs. Fourfold or greater increases in NA titers were noted in each of the participants, involving recognition of one to five of the nine strains tested. In some patients these NA titer changes appeared as discrete episodes of immune responses, while in others there may have been either multiple episodes or continuous evolution of the NA responses. The data indicate that changes in NA specificity occur during HIV-1 infection, which may result from the occurrence of neutralization escape mutation. The use of PVs for the study of phenotypic characteristics of envelope glycoproteins should facilitate the study of neutralization escape mutation in HIV-1 infection.

Base Sequence↗
PubMed1998

Mutations in both gp120 and gp41 are responsible for the broad neutralization resistance of variant human immunodeficiency virus type 1 MN to antibodies directed at V3 and non-V3 epitopes.

The escape of human immunodeficiency virus type 1 from effects of neutralizing antibodies was studied by using neutralization-resistant (NR) variants generated by growing the neutralization-sensitive (NS) wild-type MN virus in the presence of human serum with neutralizing antibodies, more than 99% of which were directed at the V3 region of gp120. The variants obtained had broad neutralization resistance to human sera, without limitation with respect to the V3 specificity of the sera. The molecular basis for the resistance was evaluated with molecularly cloned viruses, as well as with pseudoviruses expressing envelope glycoproteins of the NS and NR phenotypes. Nucleotide sequence analyses comparing NS and NR clones revealed a number of polymorphisms, including six in the V1/V2 region, two in C4/V5 of gp120, three in the leucine zipper (LZ) domain of gp41, and two in the second external putative alpha-helix region of gp41. A series of chimeras from NS and NR env genes was constructed, and each was presented on pseudoviruses to locate the domain(s) which conferred the phenotypic changes. The neutralization phenotypes of the chimeric clones were found to be dependent on mutations in both the C4/V5 region of gp120 and the LZ region of gp41. Additionally, interaction between mutations in gp120 and gp41 was demonstrated in that a chimeric env gene consisting of a gp120 coding sequence from an NS clone and a gp41 sequence from an NR clone yielded a pseudovirus with minimal infectivity. The possible significance of predicted amino acid changes in these domains is discussed. The results indicate that polyvalent antibodies predominantly directed against V3 can induce NR through selection for mutations that alter interactions of other domains in the envelope complex.

Amino Acid Sequence↗
PubMed1996

Annual influenza vaccination: immune response in patients over 10 years.

OBJECTIVE: To determine the effect of repeated annual influenza immunization on the host's serum antibody. DESIGN: Ten year observational study with cohort design. SETTING: Cystic Fibrosis Center at St. Vincent's Hospital and Medical Center, New York City, NY. PATIENTS: Thirty-eight children and young adults with cystic fibrosis (CF). MEASUREMENTS: Serum hemagglutination inhibition (HI) antibody titers were determined at the time of vaccination and 4 weeks later each year in the fall before the influenza epidemic. Shwachman scores were determined each year. RESULTS: While the pre-vaccination and post-vaccination geometric mean serum HI antibody titers varied from year to year, no upward or downward trend was evident over the 10 year period. The reciprocal of the post-vaccination geometric mean HI titers ranged annually from 32 to 74 for the influenza A (H3N2) vaccine strains, from 53 to 133 for the influenza A (H1N1) strains, and from 18 to 174 for influenza B strains. In addition, the majority of vaccinees had a presumably protective post-vaccination serum HI titer > or = 1:40 each year for all three vaccine strains. The initial mean Shwachman score of the group was 77. The final score of 76 after 10 years was not significantly different. CONCLUSIONS: Annual influenza vaccination appears to regularly induce presumably protective serum antibody levels in most CF children and young adults studied over a 10 year period.

Adolescent↗
PubMed1995

Preparation and characterization of human HIV type 1 neutralizing reference sera.

Reference neutralizing antibody (NA) reagents are needed for laboratories to be able to compare results of neutralization assays that will be used to monitor HIV-1 vaccine recipients. In an effort to establish such reference reagents two asymptomatic, seropositive patients were identified with medium to high amounts of cross-reactive NA activity against a number of HIV-1 strains. Sera obtained from each individual at three or four sequential phlebotomies were pooled, and the two pools were each distributed in > 3000 aliquots into glass ampoules and lyophilized, and the ampoules were flame sealed. An HIV-1 antibody-negative reference serum was prepared in a similar fashion after pooling serum from four individuals. Ampoules were tested for uniformity of fill, sterility, moisture content, residual oxygen, stability, infectivity, and presence of antibody. An international collaborative study was conducted to determine the potency of the samples in six laboratories, each using their own neutralization assays and reagents. The results indicated reasonable consistency between laboratories and that both sera have sufficient titers against a variety of strains for use as reference reagents. These reference sera have been included in the World Health Organization (WHO) AIDS Reagent Project and are available through the three AIDS reagent repositories.

AIDS Vaccines↗
PubMed1992

Variable infections with and serologic responses of rabbits to five different HIV-1 strains, including one neural tissue isolate.

The infectivity of different strains of HIV-1 in rabbits was investigated. The HIV-1RF and HIV-1MN inocula induced anti-envelope antibodies detectable by Western blot, and in the case of HIV-1RF, these antibodies were also detectable by ELISA. The peripheral blood lymphocytes (PBL) and lymph nodes from rabbits inoculated with HIV-1IIIB, HIV-1MN and HIV-1Z3, were positive for virus by culture and by polymerase chain reaction (PCR). HIV-1BRVA, originally isolated from a patient with AIDS dementia, infected the brain of the inoculated rabbit, as indicated by both virus culture and PCR. In this case PCR was positive using four different primer pairs. Throughout the study, rabbits showed no clinical signs of HIV-1 infection and no remarkable histopathology was observed in the tissues examined. The apparent differences in infectivity and tissue tropism of the five HIV-1 strains demonstrated here provide additional evidence that the rabbit may serve as a useful model for studying HIV-1 infection and pathogenesis.

Animals↗
PubMed1991

High prevalence of antibodies to the gp120 V3 region principal neutralizing determinant of HIV-1MN in sera from Africa and the Americas.

Neutralizing antibodies (NA) against HIV-1MN and HIV-1IIIB, and antibodies binding to synthetic peptides (BA) derived from the gp120 envelope V3 region principal neutralizing determinants (PND) of the HIV-1MN, HIV-1IIIB, and HIV-1Z3 virus strains were assayed in HIV-1 antibody-positive sera from the United States, Haiti, Brazil, Zaire, and Zimbabwe. The ability of soluble PND peptide to block neutralization of the corresponding virus by representative sera was also tested. In each country, NA and BA titers were highest against the HIV-1MN strain, and compared with other countries, NA and BA titers against HIV-1MN were higher in sera from the United States and Haiti. When NA titers were compared with BA titers against either HIV-1MN or HIV-1IIIB, no correlation was found for the HIV-1IIIB strain, but there was a significant correlation for HIV-1MN. Addition of the HIV-1MN strain peptide to a neutralization assay for HIV-1MN resulted in a four- to tenfold reduction in NA titers in sera from the United States, Zaire, and Brazil. The results suggest that HIV-1MN and closely related variants are prevalent in many parts of the world, and that antibodies directed against the PND account for most of the neutralizing activity in sera of infected individuals.

Africa↗
PubMed1991

Lack of evidence for HIV-2 infection among at-risk individuals in Brazil.

Recent reports have indicated the possibility that HIV-2 has been introduced into groups at risk for AIDS in Brazil. We studied sera collected in 1987 and 1988 from 1,821 at-risk individuals from diverse regions in Brazil. Of the 1,821 sera, 367 (20%) were confirmed as being positive for HIV-1 antibodies by enzyme-linked immunosorbent assay (ELISA), immunofluorescence (IF), and Western blot. An additional 33 (2%) sera displayed some reactivity to HIV-2-infected cells by IF. All 33 sera were subsequently tested in HIV-1 and HIV-2 Western blots as well as an ELISA using HIV-1- or HIV-2-specific peptides. All sera were confirmed as positive for HIV-1 and negative for HIV-2 antibodies in both assays. We conclude that caution should be used in the interpretation of serologic cross-reactivity between HIV-1 and HIV-2 and that there is no evidence that HIV-2 has entered groups at risk for HIV infection in Brazil.

Blotting, Western↗
PubMed1990

Effects of interferon-alpha in patients with AIDS-associated Kaposi's sarcoma are related to blood interferon levels and dose.

Definition of improved therapeutic regimens of interferon-alpha (IFN-alpha) for the treatment of Kaposi's sarcoma (KS) would be useful since currently recommended doses are sometimes associated with unacceptable toxicity. IFN concentrations were measured in serum samples from men with AIDS-associated KS who were enrolled in a trial of IFN-alpha alone (16 patients) or a trial of IFN-alpha combined with zidovudine (25 patients). Analyses were done to examine the relationship between the dose of IFN-alpha, blood level of IFN, and the patient's clinical response to treatment. There was no correlation between dose of zidovudine given and response. As expected, there was a high correlation between dose of IFN-alpha and blood level in both studies (p less than 0.001). Furthermore, we found relationships between clinical response and both dose of IFN-alpha and blood level achieved. In the two studies combined, among men with greater than 200 CD4+ cells/mm3 of blood at baseline on average daily doses of greater than or equal to 10 million international units (MIU) of IFN-alpha, 13/19 (68%) responded compared to 6/17 (35%) on less than MIU (p = 0.05). Similarly, of men with IFN blood levels greater than or equal to 100 IU/mL 12/16 (75%) responded compared to 7/20 (35%) of those with blood levels less than 100 IU/mL (p = 0.02). The dose and blood levels of IFN achieved and maintained may be important factors in determining responses of KS. Additional clinical trials of IFN-alpha treatment of KS at doses about 10 MIU/day appear warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Synergistic effect of ganciclovir and foscarnet on cytomegalovirus replication in vitro.

Ganciclovir and foscarnet possess substantial activity against cytomegalovirus. Both exhibit dose-limiting toxicity, which reduces their clinical usefulness. We demonstrated synergistic inhibition of cytomegalovirus replication in vitro by ganciclovir and foscarnet. Reduced-dose combination therapy may provide a means to treat patients with cytomegalovirus infection while reducing drug toxicity.

Cytomegalovirus↗
PubMed1990

Human immunodeficiency virus neutralizing antibodies in sera from North Americans and Africans.

Neutralizing antibodies (NAs) against four isolates of human immunodeficiency virus type 1 (HIV-1) were assayed in HIV-1 antibody positive sera from the United States, Haiti, Zimbabwe, and Zaire. Overall, there were NAs detected in 95, 81, 60, and 73% of sera with reciprocal geometric mean titers (GMTs) of 626, 23, 10, and 20, respectively, against HIV-1MN, HIV-1IIIB, HIV-1RF, and HIV-1Z3. Sera from North America had significantly higher NA titers against HIV-1MN. In each country, the highest antibody titers observed were against the MN strain. Otherwise, sera from the U.S. neutralized most strongly HIV-1IIIB, sera from Zaire neutralized most strongly HIV-1Z3, and sera from Zimbabwe had equal titers against all three viruses. The differences between countries were reflected in analyses of NA titers of subgroups classified on the basis of clinical status, indicating that the differences were not likely to be related to differences in clinical status of the patients being tested. Some of this antigenic variation is reflective of known genetic diversity, while some is not. The results suggest that undefined preserved and variable regions containing neutralization epitope(s) exist. These data do not indicate a need to define antigenic subtypes of HIV-1 at present. The existence of conserved neutralization epitope(s) may indicate the potential for broad immunogenicity of appropriately selected vaccine antigens.

AIDS-Related Complex↗
PubMed1989

Allogeneic bone marrow transplantation, zidovudine, and human immunodeficiency virus type 1 (HIV-1) infection. Studies in a patient with non-Hodgkin lymphoma.

Human immunodeficiency virus type 1 (HIV-1)-infected patients with non-Hodgkin lymphoma are classified as having the acquired immunodeficiency syndrome (AIDS). Allogeneic bone marrow transplantation is a successful therapy for patients with lymphoma who have a poor prognosis. Combined therapy with allogeneic bone marrow transplantation and the antiviral drug zidovudine has the potential advantage of protecting the new donor hematopoietic-lymphoid and monocyte-macrophage cells from HIV-1 infection. A 41-year-old man infected with HIV-1 who had lymphoma was treated with high-dose cyclophosphamide and total body irradiation followed by allogeneic bone marrow transplantation. Before transplantation he received high-dose zidovudine for 2 weeks (5 mg/kg body weight intravenously every 4 hours) and after transplantation he received a lower maintenance dose (1.33 mg/kg body weight intravenously every 4 hours). No untoward toxicities attributable to zidovudine were observed. Bone marrow engraftment occurred on day 17. Chromosome and restriction fragment length polymorphism analyses demonstrated complete chimerism. Peripheral blood mononuclear cells and bone marrow samples were negative for HIV-1 by culture and polymerase chain reaction gene amplification 32 days after transplantation. The patient died 47 days after transplantation because of tumor relapse. Analysis of autopsy tissue showed no evidence of HIV-1 by either culture (brain, bone marrow, lymph node, and tumor specimens) or by polymerase chain reaction gene amplification for HIV-1 RNA and DNA sequences (brain, bone marrow, heart, kidney, liver, lung, rectosigmoid, spleen, and tumor specimens). Immunologic monitoring showed loss of HIV-1 antibody. Adoptive immunologic transfer was shown to be present to both tetanus and diphtheria antigens. Our case suggests that the HIV-1-infected recipient cells may have been eradicated secondary to the bone marrow ablative chemo-radiotherapy and that zidovudine may be able to prevent the establishment of HIV-1 infection in donor hematopoietic-lymphoid cells.

Adult↗
PubMed1989

A phase I trial of recombinant human interferon-gamma in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS).

A Phase I study of recombinant interferon-gamma (rIFN-gamma) was conducted to determine the toxicity and pharmacokinetics of this lymphokine in acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma (KS). Sixteen patients with AIDS/KS were entered into a fixed-dose trial at either 0.001, 0.01, 0.1, or 1.0 mg/m2 of rIFN-gamma. rIFN-gamma was initially administered either as a single 24-hr continuous iv infusion or as a single im injection, followed 4 days later by a 10-day course of daily therapy by the same route. Following a 1-week washout period, this sequence of administration was then repeated, with the drug given by the alternate route. Pharmacokinetic analysis of the 1.0-mg/m2 group revealed that peak serum levels of up to 153 U/ml occurred 2-4 hr after im injection and that steady-state levels of up to 40 U/ml were reached approximately 7-12 hr after beginning iv infusion. Dose-related toxicities in this trial included fever, headache, fatigue, nausea, and hepatitis, all of which were most severe at the two highest doses. Dose-dependent depression of the total white blood-cell (WBC) count, affecting both granulocytes and lymphocytes, was the most common laboratory abnormality. Natural killer (NK)-cell activity was slightly enhanced at a dose of 0.1 mg/m2 but suppressed at 1.0 mg/m2 of drug; monocyte-mediated cytotoxicity, in contrast, was significantly increased only at the highest dose. No dose-related changes were noted in KS lesions, HLA-DR expression by peripheral blood mononuclear cells, lymphocyte blastogenesis, or the ability to culture cytomegalovirus (CMV) from body fluids. We conclude that a maximally tolerated dose (MTD) for this drug is in the range of 0.1-1.0 mg/m2 and that at least modest evidence of systemic immunomodulation may be seen when rIFN-gamma is given at doses at or near this MTD.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Quantitation of poliovirus antigens in inactivated viral vaccines by enzyme-linked immunosorbent assay using animal sera and monoclonal antibodies.

Recent advances in methods for the manufacture of inactivated poliovirus vaccines have resulted in increased vaccine immunogenicity. In conjunction with this capability it is important to have available highly sensitive and quantitative potency assays. The potential suitability of enzyme-linked immunoassay (ELISA) was evaluated using animal sera with neutralizing antibodies or neutralizing monoclonal antibodies for antigen detection in potency tests. The monoclonal antibodies developed, which bound D antigen but not C antigen, were neutralizing unless relatively weakly reactive. Those that bound C antigen only were non-neutralizing. Those that bound both C and D antigens were sometimes neutralizing. D-specific and D/C-specific neutralizing monoclonal antibodies against type-2 poliovirus protected mice on passive immunization against paralytic disease and death from the MEF strain virus. Potency measurements by ELISA using either D-specific neutralizing monoclonal antibodies or type-specific goat sera for antigen detection were sensitive and precise. Tests using C-specific monoclonal antibodies for antigen detection indicated that increased C antigen content may result in falsely elevated reactivities of animal sera with some vaccines. Monoclonal antibodies may be useful ELISA reagents for IPV potency testing.

Animals↗
PubMed1989

Relation of chronic disease and immune response to influenza vaccine in the elderly.

The ability of elderly patients to mount an adequate immune response to influenza vaccine has been debated. We studied the serum haemagglutination inhibition (HI) antibody response in elderly persons to determine whether different degrees of chronic illness were a critical factor in immune response. In autumn 1986, trivalent split virus vaccine was used to immunize 87 healthy ambulatory elderly adults and 53 institutionalized elderly adults. The pre-vaccination health status of the healthy elderly group was significantly better as measured by the incidence of chronic disorders and drug use (p less than 0.02) and by the Chronic Health Evaluation component of the APACHE severity of disease classification (p less than 0.001). No group differences were observed in serum HI antibody after immunization with the trivalent influenza vaccine. However, in 28 patients from each group who received the monovalent A/Taiwan/86(H1N1) vaccine 1 month after the trivalent vaccine, the percentage with a postvaccination HI titre greater than or equal to 40 was 57% (16 of 28) for the healthy elderly vs 7% (2 of 28) for the institutionalized elderly (p = less than 0.001). Geometric mean postvaccination HI titres were 31 and 13, respectively (p = 0.004). We concluded that the institutionalized elderly in our study mounted an inferior immune response against the new heterotypic influenza A/Taiwan strain when compared to healthy elderly adults. The Chronic Health Evaluation score may be an effective predictor of a poor immune response to new influenza vaccine strains in the elderly. Increasing age per se and lack of a history of prior influenza immunization did not adversely affect the development of protective levels of serum antibody.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1989

Secretory immunoglobulin A antibody response is conserved in aged mice following oral immunization with influenza virus vaccine.

Parenteral immunization of BALB/c mice at 3 months of age with inactivated influenza virus vaccine elicited a haemagglutinin (HA)-specific serum IgG antibody response. The magnitude of this response declined with advancing age at the time of vaccination. By contrast, HA-specific IgA and IgG antibody levels observed in lung lavage fluids of mice immunized at 1 and 2 years of age were comparable to those of 5 month old mice when inactivated influenza virus vaccine was administered intragastrically. The secretory immune response was not fully developed in the first 3 weeks of life. However, the HA-specific IgA and IgG responses to oral vaccination in sera were reduced in 1 or 2 year old mice when compared to 5 month old mice. These data demonstrated the preservation of the virus-specific secretory IgA response in the pulmonary fluids of aged mice after oral vaccination with inactivated influenza virus vaccine. An age-dependent difference of systemic and mucosal immunity was evident in orally immunized mice.

Aging↗
PubMed1988

Epstein-Barr virus in the bone marrow of patients with aplastic anemia.

STUDY OBJECTIVE: To determine whether Epstein-Barr virus is present in the bone marrow of patients with aplastic anemia. DESIGN: Assay of fresh and fixed bone marrow specimens for Epstein-Barr virus using immunofluorescence for nuclear antigen, Southern analysis with an Epstein-Barr virus specific probe, and in-situ hybridization. SETTING: Governmental medical referral center. PATIENTS: Five patients were studied prospectively: three who previously had infectious mononucleosis, one with a recent viral pneumonitis, and one who was asymptomatic. Stored DNA samples from other patients with aplastic anemia were also screened. MEASUREMENTS AND MAIN RESULTS: Epstein-Barr virus DNA and protein were detected in the bone marrow of 5 patients studied prospectively and in 1 of 40 patients studied retrospectively. As estimated by in-situ hybridization, about 3% to 5% of marrow cells were infected with virus in those patients who had not received acyclovir. In contrast, Epstein-Barr virus DNA was not detected in peripheral blood DNA of these patients, nor were Epstein-Barr virus proteins or DNA found in the bone marrow of normal donors, patients with other hematologic diseases, or in 1 patient with acute infectious mononucleosis. Analysis of DNA fragments by hybridization with Epstein-Barr virus probes showed a pattern dissimilar to the type of Epstein-Barr virus usually associated with infectious mononucleosis. CONCLUSIONS: Aplastic anemia may be associated with Epstein-Barr virus more commonly than suspected by history. Localization of the virus in the bone marrow supports a causative role for Epstein-Barr virus in bone marrow failure.

Adolescent↗