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M S McGrath

Publications and source records attributed to M S McGrath.

At least 19 recordsLinked to original sources
PubMed1992

Large-cell "mixed-phenotype" lymphoma in AIDS. Identification of a CD5-expressing subset of B-cell non-Hodgkin's lymphoma.

We have characterized cells from an AIDS-associated non-Hodgkin's lymphoma (NHL). We found a malignant CD5+ B cell (approximately three-fourths of cells), with the balance of cells comprised of T cells having an activated phenotype. The lymphoma was unusual, in that all cells bear "T-lineage" markers, CD3 and CD5, and "B-lineage" markers, CD19 and CD20. Thus, conventional immunohistologic techniques were insufficient to type this mixture of cells; single-cell analysis was required. These "mixed-phenotype" lymphomas may occur frequently in AIDS-associated NHL. Our results show striking similarity to those obtained in the analysis of certain murine CD5+ B-cell lymphomas, suggesting that the study of lymphomagenesis in the mouse may aid in the understanding of AIDS-associated NHL.

Antigens, CD↗
PubMed1992

Acquired immunodeficiency syndrome-associated T-cell lymphoma: evidence for human immunodeficiency virus type 1-associated T-cell transformation.

The majority of lymphomas in the setting of acquired, iatrogenic, or congenital immunodeficiencies are B-cell lymphoproliferations. We describe a rare T-cell lymphoma in a fulminantly ill patient infected with human immunodeficiency virus type 1 (HIV-1). The T-cell nature of the process was defined genotypically (monoclonal T-cell receptor beta-chain [CT beta] rearrangement) and phenotypically (CD45RO+, CD4+, CD5+, CD25+, CD8-, CD3- and negative for a variety of B-cell and monocyte markers). The CD4+, CD25+ (interleukin-2 receptor [IL-2R]) phenotype with production of IL-2 and IL-2R RNA is analogous to human T-lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATLL); however, no HTLV-1 could be detected. Southern blot analysis did demonstrate monoclonally integrated HIV-1 within the tumor genome. Furthermore, the tumor cells were producing HIV p24 antigen as shown by immunohistochemistry. This is the first case of acquired immunodeficiency syndrome (AIDS)-associated non-Hodgkin's lymphoma in which HIV-1 infection may have played a central role in the lymphocyte transformation process.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Human immunodeficiency virus-infected monocyte-derived macrophages express surface gp120 and fuse with CD4 lymphoid cells in vitro: a possible mechanism of T lymphocyte depletion in vivo.

Monocyte-derived macrophages (MDM) infected in vitro with a macrophage-tropic strain of human immunodeficiency virus (HIV) fused with uninfected, CD4-expressing T lymphoblastoid cells, but not with a subclone of these cells lacking surface CD4. Infected MDM also fused with uninfected autologous and heterologous MDM. Recombinant soluble CD4 protein (rsCD4) (10 micrograms/ml) and full-length recombinant glycosylated gp120 (20 micrograms/ml) each inhibited fusion by 94-99%; the inhibition was dose-dependent. The N-terminal portion of gp120 did not inhibit syncytium formation. Fusion was also inhibited by a monoclonal antibody to an epitope which binds gp120 (S3.5), but not by antibody to an epitope not involved in gp120 binding (OKT4). HIV-infected MDM specifically bound fluorescein-conjugated rsCD4, and virus could be visualized budding from the surface of these cells. HIV-infected MDM express viral gp120 on their surface and fuse with CD4-bearing cells in a fashion similar to lymphoid cells. Macrophages may contribute to CD4 lymphocyte depletion in vivo by this fusion mechanism.

Antibodies, Monoclonal↗
PubMed1992

Effects of dimethyl prostaglandin A1 on herpes simplex virus and human immunodeficiency virus replication.

We have investigated the direct effect of dimethyl prostaglandin A1 (dmPGA1) on the replication of herpes simplex virus (HSV) and human immunodeficiency virus type 1 (HIV-1). dmPGA1 significantly inhibited viral replication in both HSV and HIV infection systems at concentrations of dmPGA1 that did not adversely alter cellular DNA synthesis. The 50% inhibitory concentration (ID50) for several HSV type 1 (HSV-1) strains ranged from 3.8 to 5.6 micrograms/ml for Vero cells and from 4.6 to 7.3 micrograms/ml for human foreskin fibroblasts. The ID50s for two HSV-2 strains varied from 3.8 to 4.5 micrograms/ml for Vero cells; the ID50 was 5.7 micrograms/ml for human foreskin fibroblasts. We found that closely related prostaglandins did not have the same effect on the replication of HSV; dmPGE2 and dmPGA2 caused up to a 60% increase in HSV replication compared with that in untreated virus-infected cells. HIV-1 replication in acutely infected T cells (VB line) and chronically infected macrophages was assessed by quantitative decreases in p24 concentration. The effective ID50s were 2.5 micrograms/ml for VB cells acutely infected with HIV-1 and 5.2 micrograms/m for chronically infected macrophages. dmPGA1 has an unusual broad-spectrum antiviral activity against both HSV and HIV-1 in vitro and offers a new class of potential therapeutic agents for in vivo use.

Animals↗
PubMed1991

Purified trichosanthin (GLQ223) exacerbation of indirect HIV-associated neurotoxicity in vitro.

A formulated preparation of trichosanthin (GLQ223, Pharmaceutical Development Group, Genelabs Inc., Redwood City, California, USA) has been shown to selectively inhibit HIV replication in vitro in lymphocytes and macrophages. In view of recent anecdotal reports of central nervous system (CNS) complications associated with trichosanthin use in some HIV-infected patients, we evaluated any potential drug effects leading to neurotoxicity using a human brain cell aggregate model. Brain cell aggregate cultures were incubated with dilutions of purified trichosanthin alone (trichosanthin), supernatants of HIV-infected macrophage cultures (S-HIV), supernatants of uninfected macrophage cultures (S-U), supernatants of purified trichosanthin-treated uninfected macrophage cultures (S-trichosanthin), or supernatants of purified trichosanthin-treated HIV-infected macrophage cultures (S-HIV-trichosanthin). Treatment with purified trichosanthin alone at up to 2 micrograms/ml, with S-U or with S-trichosanthin, produced no morphological signs of toxicity to brain cell aggregate cultures. S-trichosanthin treatment at 2 micrograms/ml did not result in a significant change in cyclic nucleoside phosphorylase (CNP) activity. Treatment of the brain aggregates with S-HIV and S-HIV-trichosanthin did, however, result in morphological alteration of the brain aggregates, with S-HIV-trichosanthin-treated brain aggregates showing the most severe damage. Although purified trichosanthin did not appear to be directly toxic to human brain aggregate cultures, trichosanthin treatment of infected macrophages may have increased the morphological alterations caused by supernatants of HIV-infected macrophages. These experimental observations may explain anecdotal reports of adverse CNS reactions in association with trichosanthin treatment of HIV-infected patients and emphasize the neurotoxic potential of any therapy targeted at HIV-infected macrophages.

Brain↗
PubMed1991

Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains.

We wanted to establish an in vitro human model for AIDS-associated dementia and pursue the hypothesis that this disease process may be a result of soluble factors produced by HIV-infected macrophages. Human brain aggregates were prepared from nine different brain specimens, and were treated with supernatants from in vitro HIV-infected macrophages (SI), uninfected macrophages (SU), infected T cells, or macrophage-conditioned media from four AIDS patients. Seven of nine treated brains exposed to SI showed peripheral rarefaction after 1 wk of incubation that by ultrastructural analysis showed cytoplasmic vacuolation. Aggregates from two of three brain cultures treated with SI for 3 wk became smaller, an approximately 50% decrease in size. The degree of apparent toxicity in brains exposed to patient-derived macrophage supernatants paralleled the proportion of macrophages found to be expressing HIV p24. Ultrastructural abnormalities were not observed in brains treated with supernatants from HIV-infected T cells, uninfected macrophages, or LPS-activated macrophages. Levels of five neurotransmitter amino acids were decreased in comparison to the structural amino acid leucine. These findings suggest that HIV-infected macrophages, infected both in vitro as well as derived from AIDS patients' peripheral blood, produce factors that cause reproducible histochemical, ultrastructural, and functional abnormalities in human brain aggregates.

AIDS Dementia Complex↗
PubMed1991

AIDS-associated polyclonal lymphoma: identification of a new HIV-associated disease process.

High-grade non-Hodgkins B-cell lymphoma is one of the principle malignancies that occurs in individuals infected with the human immunodeficiency virus (HIV-1). Immunoblastic lymphomas that arise in immunosuppressed transplant patients have been described as both monoclonal and polyclonal, and occur in association with Epstein-Barr virus (EBV) infection. To test whether polyclonal lymphoma occurred in patients with AIDS we studied tumors from multiple sites in three patients who died with widespread AIDS-associated large cell or large cell immunoblastic lymphoma. All biopsy specimens contained invasive lymphoma. Tumor cells were mature IgM-positive immunoblasts by immunohistochemical analysis, with the same B-cell phenotype observed in all tumor sites. Only a minority of sites from all patients analyzed were monoclonal as measured by immunoglobulin gene rearrangements, with one case having several foci of monoclonal disease with other histologically identical metastases showing no evidence of monoclonal proliferation. Similar to the transplant-associated polyclonal B-cell proliferations. EBV gene sequences were present in multiple sites from one autopsy. In the other two autopsies, polyclonal B-cell proliferations occurred in the absence of EBV involvement except at one site, where a minor clone of EBV-infected cells was found. In contrast to HIV-associated Burkitt's lymphoma, no c-myc rearrangements were found at any site. These studies describe the occurrence of polyclonal lymphoma in AIDS and suggest that EBV-negative polyclonal lymphoma may be a distinct disease entity unique to HIV-infected individuals.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Molecular pathogenesis of AIDS-associated non-Hodgkin's lymphoma.

The pathogenesis of non-Hodgkin's lymphoma (NHL) in HIV-infected individuals is currently poorly understood; however, recent molecular studies have subdivided these lymphomas into distinct molecular pathologic entities. Similar to endemic and sporadic Burkitt's lymphoma, monoclonal B-lymphoma subsets were found to be infected with Epstein-Barr virus (EBV) or have c-myc gene rearrangements, suggesting a role for EBV infection or chromosomal translocation in a subset of AIDS NHLs. Similar to lymphomas that occur in immunosuppressed transplant patients, EBV-positive polyclonal lymphomas also have been described. Unique to HIV-infected patients, however, is the subset of polyclonal B-cell lymphoma with no evidence for EBV infection. Based on these molecular studies, it is apparent that the AIDS NHLs represent a heterogeneous set of diseases with a number of pathogenic processes involved in lymphomagenesis.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Compound Q.

Explore the source record for details and available documents.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Full-length recombinant CD4 and recombinant gp120 inhibit fusion between HIV infected macrophages and uninfected CD4-expressing T-lymphoblastoid cells.

Human immunodeficiency virus-(HIV) infected monocyte-macrophages may contribute to the pathogenesis of HIV-associated immune deficiency and dysfunction by acting as a target and potential reservoir for the virus in vivo, and by functioning abnormally following infection. We have shown that HIV-infected macrophages fuse with uninfected CD4-expressing lymphoid cells in vitro; this may provide an additional mechanism for CD4 lymphocyte depletion in vivo. We report here the inhibition of syncytium formation between HIV-infected macrophages and uninfected CD4-expressing T-lymphoid cells by monoclonal antibody S3.5, directed against an epitope of CD4 involved in binding HIV gp120, by a recombinant protein that comprises the full-length extracellular domain of the CD4 molecule, and by recombinant full-length HIV envelope glycoprotein, gp120. These results indicate that both molecules (gp120 and CD4) are critical to the fusion process, and suggest that gp120 is expressed on the surface of HIV-infected monocyte-macrophages.

Antibodies, Monoclonal↗
PubMed1990

Effects of GLQ223 on HIV replication in human monocyte/macrophages chronically infected in vitro with HIV.

GLQ223 is a formulated version of tricosanthin, a single-chain ribosome-inactivating protein that was shown in earlier studies to inhibit human immunodeficiency virus (HIV) replication in T-lymphoblastoid cells and to decrease HIV p24 levels in HIV-infected monocyte-derived macrophages as measured by flow cytometry. The current studies were performed to test the selectivity of the observed inhibitory effects on HIV replication in chronically infected macrophages infected in vitro. Peripheral blood-derived monocyte/macrophages were infected in vitro and cultivated in suspension for at least two weeks prior to GLQ223 treatment. Anti-HIV effects were quantitated by measurement of cytoplasmic HIV p24, by both enzyme-linked immunosorbent assay (ELISA) and flow cytometry and HIV RNA levels were measured by slot blot analysis. Incorporation of [3H]leucine into trichloroacetic acid- (TCA) precipitable protein was also evaluated as an index of nonspecific inhibitory effects mediated by the compound in infected and uninfected cultures. Five days after a single 3-h treatment with GLQ223 there was a concentration-dependent decrease in all measurable HIV parameters within infected cultures. The anti-HIV effects persisted at least 28 days without evidence for increasing HIV expression. GLQ223 treatment of parallel uninfected macrophage cultures showed no significant inhibition of tritiated leucine uptake. These experiments demonstrate that a single pulsed exposure with GLQ223 of macrophages infected with HIV in vitro caused a sustained, concentration-dependent decrease in both HIV p24 antigen levels as well as HIV RNA without causing measurable toxicity in uninfected cultures.

Antiviral Agents↗
PubMed1990

Anti-idiotypic antisera raised against monoclonal antibody specific for a p24 gag region epitope detects a common interspecies idiotype associated with anti-HIV responses.

One potential strategy for the control of human immunodeficiency virus (HIV) infection is immune network manipulation using anti-idiotypic antibodies: this study was undertaken to demonstrate experimentally the potential of such an approach which, in a more highly evolved form, could be used for the treatment of the acquired immune deficiency virus (AIDS) and related disorders. Anti-idiotypic antibodies were generated in rabbits against a murine monoclonal antibody identifying an epitope on the p24 gag core protein of HIV. After extensive absorption on affinity columns to remove isotype- and allotype-specific antibodies, the purified anti-idiotypic antibody preparation was shown to have specific complementarity with the immunizing mouse monoclonal antibody. This anti-idiotypic antibody was also shown to recognize a common idiotype associated with HIV-specific antibodies from both humans and chimpanzees infected with the AIDS virus. In addition a group of rats immunized with the anti-Id responded with significant antibody titers to recombinant derived p24 gag. These data indicate that at least a subpopulation of these polyclonal anti-Id antibodies structurally mimics an HIV gag region epitope and suggest that immunoregulation by anti-idiotypic antibodies may have therapeutic utility for the AIDS epidemic.

Animals↗
PubMed1989

The clinical significance of human immunodeficiency virus type 1-associated paraproteins.

We observed and characterized paraproteins present in the serum of seven human immunodeficiency virus type 1 (HIV-1)-infected individuals. Immunoglobulin (Ig) subclass typing performed on these paraproteins identified five as IgG1 kappa, one as an IgG3 lambda, and one as an IgA lambda. The IgG1 kappa paraproteins, purified by high-pressure liquid chromatography, contained the majority of anti-HIV-1 antibody reactivity present in the five serum specimens (ranging from 1:5,000 to 1:500,000) as demonstrated by immunoblot. All five IgG1 paraproteins had at least two light chain species as demonstrated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and the antibodies were reactive with multiple HIV-1 viral antigens. In contrast, the electrophoretically purified IgG3 lambda and IgA lambda paraproteins did not react with HIV-1 antigens and only one light chain species was detected by SDS-PAGE. The subsequent clinical evaluation of these patients following the initial observation of paraproteinemias failed to correlate the presence of paraproteins with the development of lymphoma over a 2 to 3 year period. These data support the hypothesis that IgG1 paraproteins present in the sera of HIV-1 infected individuals reflect a normal albeit exuberant polyclonal immune response to HIV-1 viral antigens. In contrast, the clinical significance of an IgG3 lambda or an IgA lambda paraprotein is unclear at present.

Antibody Specificity↗
PubMed1989

IgM secreted by human T lymphoma virus-I-infected and transformed human B cell clones recognize a 66-kilodalton host-encoded protein.

It has previously been determined that transformed human B cells may be infected by and retain integrated human T cell lymphotropic virus, type I (HTLV-I). Although HTLV-I is primarily associated with transformation of human T lymphocytes, immortalized B cell populations have arisen after cocultivation of normal B cells and irradiated HTLV-I-infected T cells. To test whether HTLV-I infection might be involved in this B cell transformation process, we characterized five independent HTLV-I-infected and -immortalized human B cell clones. All five clones contained clonal HTLV-I integrations, expressed cell surface IgM, and secreted IgM in quantities varying from 0.1 to 4.0 micrograms/ml. Immunoblotting and immunoprecipitation of metabolically labeled cell lysates failed to detect synthesis of HTLV-I gag, env, or tat gene products, and cellular RNA dot blot analysis detected varying levels of HTLV-I gene transcripts in only three of the five clones. The secreted IgM from culture supernatants were affinity purified, and were found to selectively immunoprecipitate an acidic protein (isoelectric point = 5.0) of 66,000 m.w. (p66) from purified radioiodinated HTLV-I virions. This p66 copurified with metabolically labelled HTLV-I-infected B cell IgM from HKA-3 cells. Although HTLV-I RNA transcripts were present at low levels, the absence of HTLV-I proteins in HKA-3 cells made it unlikely that p66 was related to the major HTLV-I envelope glycoprotein, gp62. Anti-idiotypic mAb directed against the IgM produced by one B cell clone (HKA-3), as well as purified HTLV-I virions (containing p66), stimulated HKA-3 cell proliferation. Preincubating the anti-Id antibody or HTLV-I with excess HKA-3 IgM abolished the binding of either to HKA-3 cells. These data suggest that HTLV-I infected cells produce a cellular protein (p66), which is incorporated into and copurifies with HTLV-I virions, and which in at least one case (HKA-3) may act as a mitogenic stimulus, potentially contributing to the HTLV-I mediated transformation process.

Antibodies, Anti-Idiotypic↗
PubMed1989

Comparative assessment of antiretrovirals in human monocyte-macrophages and lymphoid cell lines acutely and chronically infected with the human immunodeficiency virus.

We compared the efficacy of 3 antiretrovirals in cultured human peripheral blood monocyte-derived macrophages and lymphoid cells infected with the human immunodeficiency virus (HIV). Zidovudine (greater than 0.01 micrograms/ml) or foscarnet (greater than or equal to 100 micrograms/ml) consistently inhibited HIV replication (p24 antigen production) in acutely infected macrophages by more than 90%; alpha interferon (1,000 units/ml) inhibited HIV replication by 88-99%. Drug efficacy was equal in lymphoid cells and monocyte-derived macrophages. However, these antiretrovirals even in high concentration only minimally inhibited chronic, established HIV infection: while zidovudine (0.01 micrograms/ml) inhibited infection by over 90% in acutely infected macrophages and lymphoid cells, 50 micrograms/ml of this antiretroviral produced only 19-55% inhibition of HIV replication in chronically infected cells. Slot-blot analysis of HIV RNA was concordant with the p24 antigen data. Acutely infected macrophages are as susceptible to the inhibitory effects of antiretrovirals as lymphoid cells; however, chronically infected macrophages (which probably constitute the main in vivo reservoir for HIV) are several orders of magnitude more resistant.

Antiviral Agents↗