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Biomedical subjects

J L Sullivan

Publications and source records attributed to J L Sullivan.

At least 91 records · Page 5Linked to original sources
PubMed1995

Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus.

In these Phase I/II open-label clinical trials, 62 persons with human immunodeficiency virus type 1 (HIV-1) infection and CD4+ cell counts < 400/mm3 received nevirapine at doses of 12.5, 50, and 200 mg/day, alone or in combination with zidovudine, 200 mg q8h. Nevirapine was well tolerated in the doses tested. Mean steady-state trough levels were 0.23, 1.1, and 1.9 micrograms/ml for the 12.5, 50, and 200 mg/day doses, respectively. Early suppression of p24 antigen levels and increase in CD4+ cell count were reversed following rapid emergence of virus less susceptible to nevirapine. Resistant strains were isolated from all participants by 8 weeks. Nevertheless, reduction of p24 antigen levels to < 50% of baseline values persisted for 12 weeks or more in four of seven persons who received 200 mg nevirapine/day in combination with zidovudine: these individuals had been antigenemic on long-term zidovudine therapy. This study demonstrates a direct relationship between drug resistance and effects on surrogate markers in HIV-1 infection.

Adult↗
PubMed1995

HIV-1-specific cytotoxic T lymphocyte responses in the first year of life.

HIV-1-specific CTL responses were prospectively evaluated in infants born to HIV-1-seropositive women to assess the capability of the young infant to generate HIV-1-specific CTL and to examine the potential role of HIV-1-specific CTL in the pathogenesis of vertical infection. Our results indicate that some young infants, and even the fetus, seem to be capable of generating virus-specific CTL responses. The detection of HIV-1-specific CTL responses varied among infants, however, with respect to timing, HIV-1 gene product recognition, and the magnitude of detectable responses; HIV-1-specific CTL responses were uncommonly detected in the first few months of life. The less consistent detection of HIV-specific CTL in early infancy contrasts with reports of the detection of HIV-1-specific CTL soon after primary infection in adults. HIV-1-specific CTL were not detected in any uninfected infants born to HIV-1-seropositive women. This description of HIV-1-specific CTL in infants may have important implications for understanding the pathogenesis of vertical HIV-1 infection and for the development of a vaccine to interrupt vertical infection.

Age Factors↗
PubMed1995

High-dose nevirapine: safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection.

Nevirapine, a potent nonnucleoside reverse transcriptase inhibitor, produces a transient antiviral effect at < or = 200 mg/day due to the selection of resistant virus. To examine if higher levels of nevirapine could produce sustained antiviral activity, its safety, pharmacokinetics, and antiviral activity at 400 mg/day were studied in 21 patients. There was a rapid reduction in immune complex-dissociated p24 antigen and serum human immunodeficiency virus RNA concentration in all patients, and 8 of 10 patients had > 50% reduction at 8 weeks. Nevirapine-resistant virus was isolated from all subjects tested at 12 weeks: The mean plasma trough level (4.0 micrograms/mL [15.8 microM]) exceeded the mean IC50 of resistant virus. Rash developed in 48% of patients and was a dose-limiting toxicity factor in 6. These data suggest that clinical testing of potent antiviral compounds that select for drug-resistant virus is justified to determine if serum levels of drug sufficient to overcome resistant virus can be attained.

Adult↗
PubMed1995

Major histocompatibility complex class I-restricted cytotoxic T lymphocyte responses to Epstein-Barr virus in children.

Epstein-Barr virus (EBV)-specific cytotoxic T lymphocyte (CTL) responses were evaluated in 9 children aged 20-35 months. Autologous EBV-transformed B lymphoblastoid cell lines were used to restimulate EBV-specific memory CTL precursors in vitro. Recognition of individual EBV gene products by bulk CTL lines was evaluated by combining CTL lines with B cell blasts infected with recombinant vaccinia constructs expressing single latent genes. CTL lines from all 9 children recognized one or more EBV latent gene products. All children demonstrated CTL responses against one or more EBV nuclear antigen 3 proteins (EBNA3A, 3B, 3C), and EBNA3C was recognized most frequently. The striking similarity between EBV-specific CTL responses described here in young children and those reported for adults suggests that the EBNA3 family of proteins and latent membrane protein 2A should be considered for inclusion in candidate EBV vaccines.

Adult↗
PubMed1995

High levels of human peripheral blood mononuclear cell engraftment and enhanced susceptibility to human immunodeficiency virus type 1 infection in NOD/LtSz-scid/scid mice.

Inbred C.B-17-scid/scid mice accept human peripheral blood mononuclear cell (PBMC) xenografts and are susceptible to human immunodeficiency virus type 1 (HIV-1) infection, but low levels of PBMC engraftment impede use of this system in HIV research. This report describes the effect of host strain background on human PBMC engraftment and HIV infectivity in scid mice. Back-crossing the scid mutation to the NOD/Lt strain (designated NOD/LtSz-scid/scid) increased the percentage of engrafted human PBMC in recipient spleens by 5- to 10-fold compared with that in C.B-17-scid/scid stock. Four weeks after human PBMC-injected mice were infected with HIV-1, 79% of NOD/LtSz-scid/scid spleens harbored replicating virus compared with only 39% of spleens in C.B-17-scid/scid mice. The NOD/LtSz-scid/scid mouse may provide a useful small animal model for studies of HIV-1.

Animals↗
PubMed1994

Localization of HIV RNA in mitochondria of infected cells: potential role in cytopathogenicity.

The intracellular distribution of HIV-1 RNA transcripts in infected cells was studied using in situ hybridization detected by electron microscopy and cellular fractionation. Although viral RNA and core protein could be detected throughout the cytoplasm and nucleus, viral RNA was found in significantly increased amounts in mitochondria relative to the cytoplasm and nucleus. In contrast, cellular poly(A) RNA or viral gag proteins were not increased in the mitochondria. A cell line containing an integrated latent genome that could be induced to express viral RNA after phorbol ester stimulation showed an increase in viral RNA accumulation in mitochondria parallel with the increase in HIV expression levels. Concomitant with HIV expression, there was a decrease in mitochondrial viability. Using immunofluorescent markers to detect probes to HIV RNA transcripts and antibodies to mitochondrial proteins simultaneously in single cells, there was an inverse relationship between the amount of viral RNA and mitochondrial integrity. High levels of viral RNA in mitochondria were found in acutely (but not chronically) infected cells. We propose that HIV RNA import into mitochondria can compromise mitochondrial function.

Cell Line↗
PubMed1994

Non-syncytium-inducing HIV type 1 isolated from infected individuals replicates in MT-2 cells.

Human immunodeficiency virus type 1 (HIV-1) isolates from six infected individuals less then 4 years of age were phenotyped for their syncytium-inducing (SI) ability in MT-2 cells. Three viral isolates that induced syncytia were detected. One SI isolate was from an individual who was in disease stage P2A,B,C and two SI isolates were recovered sequentially from another individual who switched from disease stage P1B to P2F. Non-syncytium-inducing (NSI) isolates were detected in two individuals who were in stage P1B of disease, and in a third individual who was in stage P2A of disease. Three sequential isolates obtained over a 2-year period from a fourth individual who progressed from disease stage P1B to P2A,B,C and subsequently died of AIDS-related disease were also found to have the NSI phenotype. To test whether NSI isolates can replicate in the absence of syncytium formation, we analyzed NSI-infected MT-2 cells for production of viral p24 antigen and expression of viral RNA by in situ hybridization. By day 12 postinfection, 6 of 7 NSI viral isolates produced 7- to 36-fold increases in p24 antigen compared to day 6, and expressed viral RNA in 13-20% of cells. A single NSI isolate that did not replicate in MT-2 cells was obtained from an individual who was asymptomatic (stage P1B). The individual rapidly progressed to symptomatic stage P2F and two sequential SI viruses were isolated. These SI isolates replicated in MT-2 cells and induced cytopathic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1994

Quantitative assessment of human immunodeficiency virus type 1 replication in human xenografts of acutely infected Hu-PBL-SCID mice.

Replication of the IIIB strain of human immunodeficiency virus type 1 (HIV-1IIIB) in CB.17 scid/scid mice reconstituted with human peripheral blood lymphocytes (Hu-PBL-SCID) was investigated. Hu-PBL-SCID mice could be infected, in a dose-dependent manner, when HIV-1IIIB was injected intraperitoneally. Replication-competent HIV-1 could be recovered from spleen, peripheral blood, bone marrow, thymus, lymph node, and peritoneal cavity, indicating the ability of the infection to spread to human tissue throughout the chimeric animals. HIV-1 infection was quantitated using p24 determination, end-point dilution culture, and polymerase chain reaction amplification. The level of HIV-1 replication in Hu-PBL-SCID mice was found to approximate the level reported in human infection. No HIV-1-specific immune response was generated to this infection, but nonspecific immune activation did occur, as also reported in human infection. Similarities therefore exist between HIV-1 infection of humans and Hu-PBL-SCID mice, which makes the latter an in vivo model in which to study HIV-1 replication.

Animals↗
PubMed1994

Normal immune function and inability to isolate virus in culture in an individual with long-term human immunodeficiency virus type 1 infection.

A detailed, longitudinal study was undertaken to investigate the immunological and virological features of an individual with hemophilia infected with human immunodeficiency virus type-1 (HIV-1) for 10 years without disease. Methods applied to serial samples of peripheral blood included Western blot analysis, neutralizing antibody assays, antibody-dependent cell-mediated cytotoxicity (ADCC) titration, HIV-1 specific cytotoxic T lymphocyte (CTL) assays, viral cultures, and PCR with sequence analysis of viral regulatory genes. Strong antibody responses against HIV-1 antigens as measured by Western blot and ADCC assays have persisted throughout infection. Repeated attempts to isolate HIV-1 using sensitive culture techniques and to demonstrate viremia with standard PCR methods have failed. Using the "booster" PCR technique, a period of viremia in peripheral blood mononuclear cells was demonstrated. Concurrent with detection of circulating virus, titers of neutralizing antibodies and circulating HIV-1-specific CTLs became measurable. Sequencing studies of a portion of the viral genome showed no significant abnormalities of the regulatory genes. In this individual, the combination of low viral load in the peripheral blood and a strong, responsive immune system is associated with long-term, disease-free coexistence with HIV-1 infection.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1994

Detection of cell-free Epstein-Barr virus DNA in serum during acute infectious mononucleosis.

Infectious Epstein-Barr virus (EBV) is shed from the oropharynx of infected hosts intermittently throughout life, but in the peripheral circulation the viral genome characteristically maintains itself in a noninfectious, cell-associated form. Sera from 125 persons with heterophil-positive acute infectious mononucleosis or EBV-associated nasopharyngeal carcinoma or who were healthy virus carriers were examined for evidence of cell-free viral DNA. EBV DNA suggesting viremia was detected in 11 (27%) of 41 infectious mononucleosis patients by polymerase chain reaction analysis but infrequently in healthy seropositive carriers and patients with nasopharyngeal carcinoma. In serial samples examined from 2 patients, serum EBV DNA was detected over a 3-day interval. Viral DNA was found in concert with one serologic marker of acute infection, EBV-specific polymeric IgA, that could affect patterns of viral spread and clinical symptomatology.

Acute Disease↗