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Biomedical subjects

M Popovic

Publications and source records attributed to M Popovic.

At least 91 records · Page 5Linked to original sources
PubMed1987

In vitro susceptibility of different human T-cell subpopulations and resistance of large granular lymphocytes to HTLV-I infection.

T4 subpopulation of T lymphocytes is the preferential target of infection with human T leukemia/lymphoma virus of subgroup I (HTLV-I). In this study we attempt to determine whether different T-cell subsets exhibit differences in susceptibility to virus infection. T cells from cord or peripheral blood were separated according to cell densities and T-cell surface markers by Percoll gradient and Sepharose anti-Fab immunoadsorbent affinity column (IAC), respectively. Separated T-cell subpopulations were infected with HTLV-I, by means of co-cultivation with irradiated virus producer cell lines (MT-2, TK). Percentages of HTLV-I-infected cells were assayed by immunofluorescence assay (IFA), using highly specific mouse monoclonal antibody (MAb) directed against HTLV-I p19 core protein. The results showed that different T-cell subpopulations separated either by Percoll or by IAC were susceptible to HTLV-I infection with the exception of large granular lymphocytes (LGL), which exhibit high cell-mediated natural cytotoxicity (CMNC). The susceptibility to HTLV-I infection of T cells with CMNC activity was further studied on established cell clones with LGL morphology. The results showed again that these cells were resistant to the virus infection. The present studies indicate that different T-cell subpopulations, irrespective of their size and of cell-surface markers, are susceptible to HTLV-I infection, with the exception of functionally mature LGL or of immortalized LGL clones.

Cell Separation↗
PubMed1987

HTLV-I--associated B-cell CLL: indirect role for retrovirus in leukemogenesis.

Serum containing antibodies to the human T-lymphotropic virus type I (HTLV-I) has been observed at a higher than expected frequency in patients with B-cell chronic lymphocytic leukemia (CLL) in an area endemic for HTLV-I. An attempt was made to determine whether the cells from patients with this leukemia were HTLV-I antigen-committed B cells that had undergone malignant transformation. Cells from two HTLV-I seropositive Jamaican patients with CLL were fused with a human B-lymphoblastoid cell line. The hybridoma cells that resulted from the fusion of CLL cells from patient I.C. produced an immunoglobulin (IgM) that reacted with the p24 gag protein from HTLV-I, HTLV-II, and HTLV-III (now referred to as HIV), but showed preferential reactivity with HTLV-I. The specific immunoglobulin gene rearrangement (IgM, kappa) in the CLL cell was demonstrated in the hybridoma cell line, indicating that the captured immunoglobulin was from the CLL cells. The IgM secreted by the fusion of CLL cells from patient L.L. reacted only with HTLV-I-infected cells and with the HTLV-I large envelope protein (gp61) on Western blots. The CLL cells from these patients appear to be a malignant transformation of an antigen-committed B cell responding to HTLV-I infection, suggesting an indirect role for this retrovirus in leukemogenesis.

Antibodies, Viral↗
PubMed1987

HTLV-III large envelope protein (gp120) suppresses PHA-induced lymphocyte blastogenesis.

The addition of inactivated preparations of purified human T cell lymphotropic virus (HTLV-III) was found to inhibit normal human lymphocyte phytohemagglutinin (PHA)-induced blastogenesis but had no effect on concanavalin A (Con A), pokeweek mitogen, or allogeneic stimulation. The inhibition was concentration-dependent and also dependent on adding the virus preparation before or at the same time as PHA. The CD4 molecule is the receptor for HTLV-III binding. Immunopurified large envelope protein (gp120) from HTLV-III was found to bind to the CD4 molecule and also inhibited PHA-induced lymphocyte blastogenesis. These results suggest that the gp120 viral protein may alter immune function by binding to the CD4 molecule, which in turn serves as an "off" signal to lymphocyte response to PHA stimulation. Alternatively, by binding to the CD4 molecule, gp120 may interfere with the interaction of this molecule with class II histocompatibility antigens on accessory cells, thus selectively suppressing PHA response.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1987

Rapid assessment of relationships among HIV isolates by oligopeptide analyses of external envelope glycoproteins.

The most variable proteins, the gp120's, of the many isolates of HIV-I can be readily compared by two-dimensional oligopeptide maps. The gp120 in a given cell line is completely stable, but the cell line defines the actual gp120 size and may induce minor peptide changes. HTLV-IIIB and LAV differ slightly from each other even when grown in the same cell line, while LAV grown in a B cell line is less related. Molecularly distant isolates have unique patterns. While anti-HTLV-IIIB gp120 antibody neutralized both HTLV-IIIB and LAV, it recognizes only the homologous HTLV-IIIB infected cells in cytotoxicity assays. Structural analysis of isolates should be helpful in defining the range of immunological reactivities among variants as a contribution to a rational approach to a vaccine against AIDS.

Cell Line↗
PubMed1987

Epidermal Langerhans cells--a target for HTLV-III/LAV infection.

Langerhans cells (LC) are bone marrow-derived, Ia+, CD1+, CD4+, ATPase+ dendritic antigen-presenting cells within the human epidermis. Since the CD4 molecule has been implicated as a receptor structure for HTLV-III/LAV (human T-cell leukemia virus/lymphadenopathy-associated virus), we asked whether LC from HTLV-III/LAV-seropositive individuals display signs of HTLV-III/LAV infection. In skin biopsies from 7/40 HTLV-III/LAV-infected persons (1 asymptomatic carrier, 2 patients with acquired immunodeficiency syndrome (AIDS)-related complex and 4 patients with AIDS), LC were the only epidermal cells to react with a monoclonal antibody specific for the HTLV-III core protein p17. A varying percentage of p17+ LC were morphologically altered with blunt dendrites and poorly demarcated cellular contours. In one of these biopsies, the presence of LC-associated viral particles characteristic of HTLV-III/LAV as well as cytopathic changes in approximately one-third of the LC population were demonstrated by electron microscopy. These results strongly suggest that LC may harbor HTLV-III/LAV. The infection of LC with this retrovirus may have deleterious consequences for the immunologic functions of this cell system and may thus contribute to both the acquisition of immunodeficiency and the infectious and neoplastic complications of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Differential susceptibility of human mononuclear cells to infection with HTLV-I.

Infection with human T-cell leukaemia/lymphoma (HTLV-I) preferentially affects T cells of the OKT-4 phenotype. The aim of the present study was to determine whether distinct T-cell subsets exhibit differences in susceptibility to virus infection. T cells from peripheral blood were separated according to cell densities by 7-step Percoll gradients. Separated T-cell subpopulations were infected with HTLV-I, using cocultivation with irradiated virus producer MT-2 cell line. Percentages of HTLV-I-infected cells and their phenotypes were assayed by immunofluorescence assay (IFA), using highly specific mouse monoclonal antibody directed against HTLV-I P-19 core protein, and other surface markers. The results showed that different T-cell subpopulations were susceptible to HTLV-I infection with the exception of large granular lymphocytes (LGL) which exhibit high cell-mediated natural cytotoxicity (CMNC).

Adult↗
PubMed1987

Monoclonal antibodies to human immunodeficiency virus: their relation to the patterns of lymph node changes in persistent generalized lymphadenopathy and AIDS.

Recently there has been much interest in using immunohistology with monoclonal antibodies (MABs) against different cells of the immune system in lymph nodes (LNs) of patients with HIV infection. The panel of these MABs is becoming increasingly extensive. In this study we report on our finding that by using a limited number of properly chosen MABs, diagnostically and prognostically relevant parameters can be acquired. One hundred and twenty-one LN biopsy specimens from patients with HIV infection were reviewed and classified according to our expanded working classification and a fifth main type of LN lesion, the small lymphocyte follicular type, was added to our earlier classification. We propose that this new type represents a transitional form between the mixed follicular type and the follicular depleted type. In the follicular type of LN lesion there is no marked change in the number of CD4 cells within the follicles and in the extrafollicular parenchyma. The reaction against the major core proteins of HIV is always positive and the number of proliferating cells is very high. The positivity is weaker in the earlier cases and stronger in the older ones. The follicular dendritic cell (FDC) network shows degenerative changes. In the hypervascular follicular type the reaction pattern with these selected MABs is very similar to the one in the follicular type. In the mixed type there are hyperplastic follicles and regressively transformed follicles in the same node. The hyperplastic follicles show a pattern similar to those in the follicular type. However, the reaction with MABs against core proteins of HIV is often markedly stronger. The number of proliferating cells is decreased markedly. Some follicles show extensive FDC network destruction. CD4 cells within the follicles and in the extrafollicular parenchyma are decreased. The regressively transformed follicles contain very few proliferating cells and the reaction with MABs against core proteins is variable, being strong in some follicles and weak in others. The small lymphocyte type contains follicles consisting mainly of small lymphocytes. These lymphocytes are of the same phenotype as those in the primary follicles. In contrast to these, however, the numbers of CD4 and Leu 7+ cells are much decreased. The reaction with MABs to core proteins is weak and limited to the germinal centres (GCs). The number of proliferating cells is strongly diminished. The FDC network, however, is well developed in most follicles. In the follicular depleted LNs there are no follicles; however, in some LNs remnants of FDC can be seen.

AIDS-Related Complex↗
PubMed1986

Virus isolation from and identification of HTLV-III/LAV-producing cells in brain tissue from a patient with AIDS.

Primary cultures from a brain biopsy specimen of a human T-cell lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) seropositive patient with progressive dementia contained small numbers of monocytoid cells and showed reverse transcriptase activity that persisted for as long as 100 days. Electron microscopy of these cells revealed the presence of HTLV-III/LAV virions. Subcultured cells removed from primary cultures by trypsinization were nonspecific esterase negative and did not express virus or show evidence of HTLV-III/LAV proviral sequences, while those remaining in the original flasks were nonspecific esterase positive and continued to produce virus. Virus from primary cultures was transmitted to peripheral blood-derived monocyte-macrophages and T cells. Virus production in T-cell cultures was transient while the monocyte-macrophages, like the primary cultures, produced virus for at least 120 days. Infection of several brain-derived cells with this and another HTLV-III/LAV isolate failed to demonstrate virus replication. These results indicate that the HTLV-III/LAV-infected cells recovered from the brain of this patient are cells of the mononuclear phagocyte series.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Functional modifications of alloreactive T cell clones infected with HTLV-I.

Two alloreactive T cell clones with anti-HLA-DR1 specificity showed significant alterations of cognitive and functional characteristics after infection with human T cell leukemia virus (HTLV-I). Similar to HTLV-I-infected lines derived from immunologically uncommitted lymphocytes, the transformed clones displayed blastogenic mixed lymphocyte culture (MLC) responses to cells carrying any of the allelic variants of human HLA-D/DR antigens, including self. Although these two clones were originally able to provide allospecific help only to B cells expressing the DR1 antigen, after infection with HTLV-I they stimulated B cells of any HLA-D/DR phenotype to produce immunoglobulin in cultures. The helper inducer activity of the transformed clones remained susceptible to the effect of monoclonal antibody anti-LDA1 that inhibits the helper function of normal human T cells. One of these clones (207TK), which before infection specifically killed DR1-positive target cells, lost its killing ability. The other clone (19TK) although originally noncytotoxic, acquired natural killer-like function after transformation. Study of the rearrangement of the genes coding for the beta-chain of the T cell antigen receptor revealed no differences between the wild (noninfected) and mutant (infected) clones. There was, however, an increased level of this message, as well as of the message encoded by the beta-chain gene of HLA-DR in the mutant clones. Such changes may be related to transacting transcriptional effects induced by the human T cell lymphotropic virus HTLV-I.

Antibodies, Monoclonal↗
PubMed1986

The role of mononuclear phagocytes in HTLV-III/LAV infection.

Cells with properties characteristic of mononuclear phagocytes were evaluated for infectivity with five different isolates of the AIDS virus, HTLV-III/LAV. Mononuclear phagocytes cultured from brain and lung tissues of AIDS patients harbored the virus. In vitro-infected macrophages from the peripheral blood, bone marrow, or cord blood of healthy donors produced large quantities of virus. Virus production persisted for at least 40 days and was not dependent on host cell proliferation. Giant multinucleated cells were frequently observed in the macrophage cultures and numerous virus particles, often located within vacuole-like structures, were present in infected cells. The different virus isolates were compared for their ability to infect macrophages and T cells. Isolates from lung- and brain-derived macrophages had a significantly higher ability to infect macrophages than T cells. In contrast, the prototype HTLV-III beta showed a 10,000-fold lower ability to infect macrophages than T cells and virus production was one-tenth that in macrophage cultures infected with other isolates, indicating that a particular variant of HTLV-III/LAV may have a preferential tropism for macrophages or T cells. These results suggest that mononuclear phagocytes may serve as primary targets for infection and agents for virus dissemination and that these virus-infected cells may play a role in the pathogenesis of the disease.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Spectrum of human T-cell lymphotropic virus type III infection in children. Recognition of symptomatic, asymptomatic, and seronegative patients.

This study was done to gain insight into the clinical spectrum and immunologic disturbances resulting from infection with the human T-cell lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) in children. Serum antibody to p41 antigen of HTLV-III and/or direct evidence of HTLV-III in lymphocytes was considered indicative of HTLV-III/LAV infection. In 36 children with HTLV-III/LAV infection, a wide clinical spectrum was noted, ranging from asymptomatic (seven children) to symptomatic, the latter including 14 children with the acquired immunodeficiency syndrome. Microcephaly was noted in five symptomatic infants. Immunologic dysfunction was noted in all symptomatic and in two asymptomatic children. Panhypogammaglobulinemia was noted in one child. Two asymptomatic children who were HTLV-III antibody negative had virologic evidence of HTLV-III infection. All of 20 mothers who were studied were HTLV-III antibody positive and had immunologic abnormalities but only nine were symptomatic, indicating that apparently healthy women may transmit HTLV-III/LAV infection to their offspring.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Type C retroviruses of the human T cell leukemia family are not evident in patients with systemic lupus erythematosus.

Type C retroviruses of the human T cell leukemia virus (HTLV) family have been implicated in immune aberrations observed in patients with leukemias, lymphomas, and the acquired immune deficiency syndrome. We have investigated whether retroviruses of the HTLV family are involved in the etiopathogenesis of systemic lupus erythematosus (SLE) by using 1) an immunoenzymatic assay to measure antibodies to HTLV-I and HTLV-III proteins in the sera of 30 patients with SLE, and 2) nucleic acid hybridization techniques (Southern transfer) to detect proviral sequences of HTLV-I, HTLV-II, and HTLV-III in DNA extracted from peripheral blood mononuclear cells of 10 of these patients. Sera from 20 normal individuals served as controls. None of the 30 sera from SLE patients or the 20 sera from normal controls had any detectable antibodies to HTLV-I or HTLV-III. Nucleic acid hybridization studies also failed to detect any HTLV proviral sequences. These results suggest that viruses of the HTLV family do not participate in the etiopathogenesis of SLE.

Antibodies, Viral↗
PubMed1986

HTLV-III/LAV viral antigens in lymph nodes of homosexual men with persistent generalized lymphadenopathy and AIDS.

The presence of core antigens of retrovirus HTLV-III/LAV, referred to as "AIDS-related virus" (AV), has been sought in lymph node samples of patients with persistent generalized lymphadenopathy (PGL, 28 patients), prodromal AIDS (1 patient) and AIDS with Kaposi sarcoma (3 patients). In 30 patients the deposition of viral antigens, detected by monoclonal antibodies to HTLV-III and LAV, could be observed within the germinal centers (GCs) primarily within the extracellular network of immune complexes, and the two patients who were negative were atypical. No AV could be found in normal tonsil or in samples with follicular hyperplasia of unknown etiology (20 cases). These findings, taken together with the ultrastructural identification of typical retrovirus particles in all 9 PGL and 2 AIDS cases studied, indicates that the network of follicular dendritic (FD) cells is an important reservoir of AV virus antigen at this site. The persistence of this retrovirus inside the GCs helps explain how the follicular hyperplasia affecting FD cells and B blasts in PGL may in progressive cases be accompanied by destruction of FD cells and gradual development of T4+ lymphopenia. T4+ T cells may circulate through the GCs and become infected with AV there. In addition, the identification of retrovirus antigen in situ may be of diagnostic value.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Genomic diversity of human T-lymphotropic virus type III (HTLV-III).

The DNA genomes of human T-lymphotropic virus type III (HTLV-III) isolated from 18 individuals with AIDS or who were at risk for AIDS were evaluated for evidence of variation. Although all of the 18 viral DNA's hybridized throughout their entire genomes to a full-length cloned probe of the original HTLV-III isolate, each of the 18 isolates showed a different restriction enzyme pattern. The number of restriction site differences between isolates ranged from only 1 site in 23 to at least 16 sites in 31. No particular viral genotype was associated with a particular disease state and 2 of the 18 patients had evidence of concurrent infection by more than one viral genotype. Propagation of three different viral isolates in vitro for up to 9 months did not lead to detectable changes in their restriction patterns. These findings indicate that different isolates of HTLV-III comprise a spectrum of highly related but distinguishable viruses and have important implications regarding the pathogenicity of HTLV-III and attempts to develop effective diagnostic, therapeutic, and preventive measures for this virus.

Acquired Immunodeficiency Syndrome↗