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Biomedical subjects

M Popovic

Publications and source records attributed to M Popovic.

At least 73 records · Page 4Linked to original sources
PubMed1989

Biological characterization of paired human immunodeficiency virus type 1 isolates from blood and cerebrospinal fluid.

Virus has been isolated from the blood and cerebrospinal fluid (CSF) of eight subjects with varying severity of human immunodeficiency virus type 1 (HIV-1) infection and from the frontal lobe of one patient with AIDS. The five patients with AIDS-related complex (ARC) and AIDS also showed neurological/psychiatric complications. With the exception of one isolate from the CSF of an asymptomatic carrier, all isolates replicated in peripheral blood mononuclear cells and monocytes after cell-free transmission. Isolates obtained from the blood of patients in late stages of HIV infection replicated in 3 (of 4) cases in H9 cells, whereas none of the blood isolates from patients in the early stages did so. The capacity of CSF isolates to replicate in H9 cells was low (only 2 of 12). Paired virus isolates from blood and CSF of the same patient could be distinguished by their replicative capacity in different cell lines, type of cytopathic effect, and protein profile as tested by radioimmunoprecipitation. The results indicate that variant viruses with distinct biological characteristics may be isolated from the blood and CSF of the same patient.

AIDS Dementia Complex↗
PubMed1989

Dipyridamole potentiates the inhibition by 3'-azido-3'-deoxythymidine and other dideoxynucleosides of human immunodeficiency virus replication in monocyte-macrophages.

Dipyridamole (DPM) is commonly used as a coronary vasodilator and inhibitor of platelet aggregation in the treatment of cardiovascular diseases. We report here that DPM potentiates the inhibitory effects of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine against human immunodeficiency virus type 1 (HIV-1) in human monocyte-macrophages. At the same concentrations, DPM does not potentiate the toxic effects of AZT on these cells or on human bone marrow (granulocyte-monocyte) progenitor cells. Since monocyte-macrophage lineage cells appear to be the major reservoir for HIV-1 in vivo, these findings suggest the possibility of using DPM or its analogues in combination chemotherapy of HIV infections.

Antiviral Agents↗
PubMed1989

Ultrastructural analysis of germinal centers in lymph nodes of patients with HIV-1-induced persistent generalized lymphadenopathy: evidence for persistence of infection.

Germinal centers play an important role in the pathogenesis of HIV-1-induced lymphadenopathy. Cell-free retrovirus particles, gag proteins of HIV-1, and cells expressing viral RNA can be detected in these areas of the lymph node. In the present study, the ultrastructural changes and the interactions of virus with different cell types of the germinal centers were investigated. We compared the alterations of lymph nodes obtained shortly after seroconversion with those seen in longstanding lymphadenopathy. The results demonstrated that germinal centers were already infected in the early phase of the disease. However, the number of cell free virions was low. During the course of the disease, large amounts of cell free virions accumulated in the germinal centers. The persistence of germinal center infection for up to 2 years was demonstrated by detecting retrovirus particles in repeated biopsy specimens. In addition, the presence of numerous small, moderately electron dense structures that might represent defective particles of HIV-1 and influence the course of the disease were described. HIV-1 was found to replicate in lymphocytes, macrophages, and follicular dendritic cells. Quite possibly, a genomic shift may occur at the time of transmission of the virus to a novel target cell, thus, germinal centers may be one of the anatomic sites where HIV-1 acquires the ability to develop into a variant with preferential tropism for a given cell type.

AIDS-Related Complex↗
PubMed1989

Cellular localization of simian immunodeficiency virus in lymphoid tissues. I. Immunohistochemistry and electron microscopy.

Simian immunodeficiency virus (SIV) is a lentivirus with genetic relatedness to the human immunodeficiency viruses (HIV-1 and HIV-2). It induces a fatal syndrome in rhesus monkeys that closely parallels the clinical course of AIDS in humans. The authors used double-labeling immunohistochemical procedures on rhesus lymph node and spleen taken during different time periods after SIV infection to localize the p27 gag protein to specific cellular immunophenotypes. In animals with follicular hyperplasia, viral protein was found associated predominantly with follicular dendritic cells. Many of these cells showed ultrastructural alterations consisting of swollen dendritic processes containing electron-dense material. Lentiviral particles were found associated with this cell type only rarely. In lymphoid tissues with other histopathologic changes, macrophages and multinucleate giant cells were the predominant cell types containing detectable quantities of viral protein; smaller numbers of p27+ lymphocytes were present. Ultrastructurally, viral particles were found within the extracellular space adjacent to tissue macrophages and within membrane-bound vacuoles of giant cells and tissue macrophages. These results show that certain histologic patterns seen during the course of infection correlate with the localization of viral antigen to specific cellular immunophenotypes and that during the disease course, viral protein is preferentially localized in sections of lymph node and spleen to cells of the macrophage and dendritic cell lineages.

Animals↗
PubMed1988

Inhibition of human immunodeficiency virus (HIV-1/HTLV-IIIBa-L) replication in fresh and cultured human peripheral blood monocytes/macrophages by azidothymidine and related 2',3'-dideoxynucleosides.

Because of the probable role of HIV-infected monocyte/macrophages in the pathogenesis and progression of AIDS, it is essential that antiretroviral therapy address viral replication in cells of this lineage. Several dideoxynucleosides have been shown to have potent in vitro and, in the case of 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC), in vivo activity against HIV. However, because these compounds must be phosphorylated (activated) in target cells, and because monocyte/macrophages may have levels of kinases that differ from those in lymphocytes, we investigated the capacity of these drugs to suppress HIV replication in monocyte/macrophages using HIV-1/HTLV-IIIBa-L (a monocytotropic isolate). In the present study, we observed that HTLV-IIIBa-L replication in fresh human peripheral blood monocyte/macrophages was suppressed by each of three dideoxynucleosides: 3'-azido-2',3'-dideoxythymidine (AZT), 2',3'-dideoxycytidine (ddC), and 2',3'-dideoxyadenosine (ddA). Similar results were observed in 5-d-cultured monocyte/macrophages, although higher concentrations of the drugs were required. We then studied the metabolism of AZT and ddC in such cells. The phosphorylation of ddC to a triphosphate moiety was somewhat decreased in monocyte/macrophages as compared with H9 T cells. On the other hand, the phosphorylation of AZT in monocyte/macrophages was markedly decreased to 25% or less of the level in T cells. However, when we examined the level of the normal endogenous 2'-deoxynucleoside triphosphate pools, which compete with 2',3'-dideoxynucleoside triphosphate for viral reverse transcriptase, we found that the level of 2'-deoxycytidine-triphosphate (dCTP) was six- to eightfold reduced, and that of 2'-deoxythymidine-triphosphate (dTTP) was only a small fraction of that found in T cell lines. These results suggest that the ratio of dideoxynucleoside triphosphate to normal deoxynucleoside triphosphate is a crucial factor in determining the antiviral activity of dideoxynucleosides in HIV target cells, and that the lower levels of dTTP may account for the antiretroviral activity of AZT in the face of inefficient phosphorylation of this compound.

Antiviral Agents↗
PubMed1988

HLA-DR is involved in the HIV-1 binding site on cells expressing MHC class II antigens.

The primary interaction of HIV-1 with the target cell involves the viral large envelope protein (gp120) and the cellular CD4 molecule. mAb reacting with portions of CD4 have been shown to block HIV-1 attachment and infection. In one of the early reports describing HIV-1 cell interaction, some mAb reacting with MHC class II Ag were also found to block infection. To investigate further a possible role for MHC class II in HIV-1 binding, a cultured T lymphocyte cell line (H-9) that expresses MHC class II molecules and PHA-stimulated PBL was exposed for various time periods to concentrated viral particles and individual HIV-1 proteins. A decrease in the ability to detect the CD4a epitope and HLA-DR was observed after the cells were exposed to virus for 15, 30, and 60 min whereas HLA-DP and HLA-DQ Ag increased or remained unchanged. After 120 min of virus exposure, the CD4a epitope remained diminished whereas HLA-DR was detected at levels found on cells not exposed to virus. mAb detecting the CD4a epitope and HLA-DR, as well as alloantisera detecting the specific HLA-DR Ag on the target cell, blocked HIV-1 binding. When immunopurified gp120 was added to PHA-stimulated and unstimulated PBL, the CD4a epitope decreased in the same manner as was observed with whole virus preparations. In contrast to exposure to the intact virus, HLA-DR expression appeared to increase. Other viral proteins, p17, p24, and a portion of the small envelope protein, gp41, had no effect on the ability to detect cell surface Ag. Thus, although CD4 is the primary receptor for HIV-1 binding, HLA-DR appears to be involved in the binding site, probably by virtue of its close proximity to the CD4 molecule on the cell surface.

Antibodies, Monoclonal↗
PubMed1988

Risk of human immunodeficiency virus (HIV-1) infection among laboratory workers.

In a prospective cohort study of 265 laboratory and affiliated workers, one individual with no recognized risk factors for human immunodeficiency virus type 1 (HIV-1) infection was HIV-1 seropositive at the time of entry into the study. Molecular analyses of two HIV-1 isolates derived in two independent laboratories from a blood sample from this worker showed that the isolates were indistinguishable from a genotypic form of HIV-1 present in the H9/HTLV-IIIB cell line. Exposure to this strain of virus most probably occurred during work with concentrated virus or culture fluids from virus-producing cell lines under standard Biosafety Level 3 containment. Although no specific incident leading to this infection has been identified, undetected skin contact with virus culture supernatant might have occurred. This worker was the only one found to be positive among the subgroup of 99 workers who shared a work environment involving exposure to concentrated virus. The incidence rate of 0.48 per 100 person-years exposure indicates that prolonged laboratory exposure to concentrated virus is associated with some risk of HIV-1 infection, which is comparable to the risk for health care workers experiencing a needle stick exposure. While none of the ten workers with parenteral exposure to HIV-1 in this cohort became infected, a worker in another laboratory did seroconvert following an injury with a potentially contaminated needle. Strict Biosafety Level 3 containment and practices should be followed when working with concentrated HIV-1 preparations, and further refinement of the procedures may be necessary.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Role of mononuclear phagocytes and accessory cells in human immunodeficiency virus type I infection of the brain.

The cells responsible for persistence of viral infection in the brains of human immunodeficiency virus type I-positive individuals are most likely mononuclear phagocytes. The infection of other cell types within the brain is presumably the result of close interactions with HIV-I-producing cells of the mononuclear phagocytic lineage. During these interactions, both direct effects from HIV-I infection of brain cells as well as indirect mechanisms (namely the response of brain cells to the presence of virus-infected cells, particularly monocytes and macrophages) should be considered. In addition, the genomic variability of HIV-I could play a role in increasing the tropism of the virus for certain cell types.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Human T-cell lymphotropic virus I and adult T-cell leukemia: report of a cluster in North Carolina.

PURPOSE: Human adult T-cell leukemia-lymphoma is a malignant, proliferative disease of CD4+ lymphocytes associated with infection with human T-cell lymphotropic virus type I (HTLV-I). Following the presentation of a patient who was infected with the virus, we undertook a study of his family members and sexual contacts to see if a cluster of infected persons could be identified. CASE REPORT: A black heterosexual North Carolina native with a history of drug abuse presented with jaundice, and pancytopenia subsequently developed. He then became hypercalcemic and leukemic, with high numbers of circulating, morphologically abnormal CD4+ lymphocytes. RESULTS: As determined by radioimmunoassay and immunoblot analyses, the serum of the index case contained antibodies against core proteins (p19 and p24) of HTLV-I. When cultured in vitro with interleukin-2, the lymphocytes expressed HTLV-I specific core proteins. The virus recovered from these T cells was transmitted to cord blood T cells, which became immortalized for continuous growth in vitro, expressed HTLV-I p19 protein, and displayed characteristic C-type particles by electron microscopy. Studies of family members and sexual contacts, all of whom were black, heterosexual central North Carolina natives, revealed five of 28 whose serum had anti-HTLV-I antibodies as determined by radioimmunoassay and immunoblot. Neither the patient nor the seropositive family/contacts had antibodies against human immunodeficiency virus proteins. Four of the six people with HTLV-I infection had no history of intravenous drug abuse. Three of the five seropositive family/contacts had circulating, morphologically abnormal lymphocytes suggestive of "preleukemic" or "smoldering" human adult T-cell leukemia-lymphoma.

Adult↗
PubMed1988

Monoclonal antibodies against human immunodeficiency virus (HIV) type 2 core proteins: cross-reactivity with HIV type 1 and simian immunodeficiency virus.

Four mouse monoclonal antibodies were developed after immunization with one human immunodeficiency virus (HIV) type 2 isolate and were tested for reactivity with different HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates in an immunofluorescence assay and by immunological blot analysis. One of them, an anti-capsid (p24) antibody, called R1C7, reacted with all HIV-1, HIV-2, and SIV isolates tested, thus identifying an epitope shared by all HIV and SIV. Another anti-capsid antibody, named A4F6, reacted with three HIV-2 isolates (HIV-2NIH-Z, LAV-2Rod, and LK001 ST9), some SIV isolates (STLV-IIIAGM, SIV-251, and SIV-309), but no HIV-1 isolates. Two anti-matrix (p16) antibodies, named R5C4 and R5F6, reacted strongly only with the HIV-2 isolates. The use of these monoclonal antibodies for rapid discrimination and identification of acquired immunodeficiency syndrome-related retroviruses is discussed.

Animals↗
PubMed1988

Immunohistochemical, electron microscopic and in situ hybridization evidence for the involvement of lymphatics in the spread of HIV-1.

To investigate the role of the lymphatic vessels and the sinus systems of the lymph node in the spread of HIV-1, we evaluated 15 lymph nodes from patients with persistent generalized lymphadenopathy (PGL). Fifteen lymph nodes taken from patients with follicular hyperplasia not related to HIV-1 infection served as controls. Immunohistochemical and in situ hybridization techniques revealed infected cells within the sinuses and the efferent lymphatics of the PGL lymph nodes. In contrast, infected cells could not be detected within the walls of the high endothelial venules nor in the areas immediately adjacent. The parenchymal side of the marginal sinus was lined by a discontinuous endothelium. Macrophages and lymphocytes were located within the gaps of this endothelium. More importantly, when the enlarged follicle extended as far as the wall of the marginal sinus, the processes of follicular dendritic cells could be seen extending through the gaps into the lumen of the sinus. This suggests that these cells could transport antigens (including HIV-1) from the sinuses directly to the germinal centers. In addition, HIV-1 particles within cytoplasmic vacuoles were seen in infected macrophages located in the submarginal zone. Positive cells were also found in the extrafollicular lymphoid parenchyma, especially in the area between the marginal sinus and the follicles. The observed distribution of the virus-positive cells within the PGL lymph nodes strongly implicates the lymphatic vessels in the spread of HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Langerhans' cells are an actual site of HIV-1 replication.

Human epidermal Langerhans' cells (LC) are HLA-DR+/DQ+, CD1+, CD4+ dendritic antigen-presenting leukocytes. Based on the observation that in certain human immunodeficiency virus type 1 (HIV-1) infected individuals, LC are the only epidermal cells to react with monoclonal antibodies against HIV-1 isolate termed human T-lymphotropic virus IIIB/83 core proteins p17 and p24, we have proposed that LC can serve as a target for HIV-1. This contention was strengthened by the ultrastructural finding of HIV-1-like particles in the close proximity of LC and by the demonstration of signs of moderate to severe LC damage. Detailed electron microscopic analysis of skin and mucosal biopsies from an AIDS patient with p17/p24-positive LC now revealed not only mature HIV-1-like virions in the extracellular space surrounding LC and in intracytoplasmic LC vacuoles, but also developmental forms of HIV-1-like particles budding from LC surface membranes. Using peripheral blood derived monocytes/macrophages as targets for HIV-1 isolation, a virus isolate, designated human T-lymphotropic virus III WR-SK/86, was recovered from skin tissue from this patient by cocultivation and identified as unique by nucleic acid hybridization analysis. These findings now conclusively show that HIV-1 replicates in and is released from LC and support the concept that antigen-presenting cells (mononuclear phagocytes, LC) can serve as a reservoir for the acquired immunodeficiency syndrome virus.

AIDS-Related Complex↗