Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activated lymphocytes have a high level of low density lipoprotein (LDL) uptake as compared to resting lymphocytes, whereas scavenger receptors for acetylated LDL (Ac-LDL) are expressed on limited number of immune cells, i.e., monocytes/macrophages. The endocytosis of LDL and Ac-LDL by mononuclear cells was studied during in vitro and in vivo HIV infection, in order to use LDL and Ac-LDL as carriers of antiviral and/or immunomodulatory drugs towards lymphocytes and monocytes. The uptake of LDL and Ac-LDL was analyzed by cytofluorimetry. LDL endocytosis in PHA/IL2-activated lymphocytes was higher than in resting lymphocytes. In vitro HIV infection of PHA/IL2-activated lymphocytes did not alter the high LDL endocytosis in lymphocytes. CD4+ and CD8+ cells. In a group of 12 symptomatic patients there was no alteration of LDL endocytosis in lymphocytes, CD4 and CD8 lymphocytes. In another group of 23 individuals, the Ac-LDL endocytosis mediated by CD14+ monocytes was unaltered in asymptomatic patients (n = 6) and in some symptomatic patients (n = 6, CD14+ cells > 100/mm3). On the contrary, in other symptomatic patients (n = 11, CD14+ cells < 100/mm3), the number of Ac-LDL+ CD14+ cells decreased, whereas their efficiency of Ac-LDL endocytosis increased as compared to those of other HIV+ patients. In conclusion, the use of lipoproteins as carriers to increase the drug delivery to CD4+ lymphocytes and to CD14+ monocytes can be envisaged, since: (i) the LDL endocytosis was not impaired in CD4 lymphocytes of HIV+ patients, and (ii) the Ac-LDL uptake by monocytes was altered only in some patients of stage IV.
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PMID:Study of LDL and acetylated LDL endocytosis by mononuclear cells in HIV infection. 754 9

Azidothymidine (zidovudine, AZT) used for treatment of HIV infection blocks the viral reverse transcriptase after phosphorylation by cellular enzymes. The first step in this reaction is the formation of AZT monophosphate, primarily catalyzed by host cytoplasmatic thymidine kinase (TK1). The activity of TK1 was determined in extracts of PHA-stimulated peripheral blood mononuclear cells (PBMCs) from 20 healthy volunteers and 49 HIV-infected patients at different stages of disease. In both groups we found a large intra- and interindividual variation of TK activity. Because TK1 expression is cell cycle regulated the proportion of stimulated cells was determined in the samples and the median thymidine kinase activity calculated. It was 3.0 pmol/mg/min x % S phase in the HIV-seronegative group and 1.1 pmol/mg/min x % S phase in HIV-infected individuals. The difference in thymidine kinase activity is statistically significant (p = 0.0001). The concentration of TK1 protein in the same extracts was also determined by immunoblotting. A positive correlation (r = 0.74) was observed between TK activity and amount of TK1 protein. The reason for this downregulation of TK is still unknown but may be related to the anergy observed in lymphocytes from HIV-infected persons. The reduced capacity for intracellular phosphorylation of AZT in HIV-infected individuals may be an important factor in the emergence of clinical AZT resistance and should also be accounted for in testing AZT resistance in vitro with PBMCs from healthy blood donors.
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PMID:Decreased thymidine kinase levels in peripheral blood cells from HIV-seropositive individuals: implications for zidovudine metabolism. 754 7

Patterns of cytokine expression were analyzed in polyclonal and antigenic responses in children with perinatal HIV infection. Responses of PBL to PMA and A23187 calcium ionophore studied in patients in different stages of HIV infection revealed reduced levels of IL-2 in HIV-infected children beginning before 6 mo of age, and age-dependent increases in expression of IL-4, IL-10, and IFN-gamma. The levels of IL-4, IL-10, and IFN-gamma expression did not differ significantly between HIV-infected and age-matched uninfected children of HIV-seropositive mothers, except for a small reduction in HIV-infected children in late stages of infection. Responses to PHA, HLA alloantigens, HIV envelope peptides T1 and P18, and tetanus toxoid were studied in PBMC derived from asymptomatic and mildly symptomatic HIV-infected children. IL-2, IFN-gamma, IL-4, and IL-5 expression was detected in PHA-stimulated PBMC from all analyzed patients. HIV-infected children who failed to respond to HLA alloantigens, tetanus toxoid, or the envelope peptides had lower numbers of CD4+ cells and expressed, on PHA stimulation, higher levels of IL-4 and IL-5 and lower levels of IL-2 and IFN-gamma than patients who responded to the antigenic stimulation. Results of these analyses suggest that cytokine expression in HIV-infected children depends on the character of the stimuli as well as the phenotype of PBMC, and indicate possible prevalence of Th2 Ag-specific responses during the progression of HIV-induced immunodeficiency.
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PMID:Cytokine patterns during progression to AIDS in children with perinatal HIV infection. 756 Nov 17

We report on the preclinical results of an immunotherapeutic approach of AIDS mediated by ex vivo propagated CD4+ and CD8+ T-cells. A mean yield of 6.23 x 10(9) lymphocytes, containing 1.82 x 10(9) CD4+, 3.23 x 10(9) CD8+ T-lymphocytes and 8.39 x 10(6) CD34+ peripheral blood progenitor cells (PBPC) were be obtained by continuous flow cytapheresis (CFC) in 15 asymptomatic HIV infected patients (CD4-count > 350/mm3). The CD4/CD8 ratio (mean: 0.53, SD: +/- 0.15) in the cell concentrates reflected the distribution of the circulating lymphocyte subsets in vivo. Absolute lymphocyte counts decreased at a mean of 404/microliter (25%) immediately after CFC but were replaced from the extravascular pool within one hour. Neither the CD4/CD8 ratio nor p24-antigen and neopterin levels did change significantly after cell separation. No alteration of the number of proviral DNA copies (1/10(3)-1/10(6)) could be detected in peripheral T-helper cells by semiquantitative PCR after lymphapheresis. Cells were cryopreserved in liquid nitrogen without substantial loss of viability or function. Ex vivo propagation of T-cells in a strictly autologous manner in the presence of PHA + IL-2 for 14d resulted in a 50-fold expansion rate (140-fold in healthy controls, p < 0.001). Viral replication could be controlled but not completely eliminated by cocultivation with autologous CD8+ T-lymphocytes as measured by limiting dilution nested PCR (NPCR). The expanded cells showed the typical phenotype of highly activated memory type T-lymphocytes (CD3+ CD45RO+ CD25+ HLA-DR+). The distribution of CD4+ and CD8+ T-cells did not reveal significant changes before and after culture indicating that both subsets were equally expanded. Functionally important membrane or intracellular epitopes which were found to be decreased in HIV infected subjects (CD7, CD55, CD59) before culture were reconstituted after ex vivo propagation of T-cells. The functional importance of the up-regulation of complement regulating epitopes (CD55, CD59) after culture could be proven by a significant inhibition of cytolysis of T-cells in the presence of autologous complement. The majority (75%) of expanded CD8+ T-cells stained positive with mAb TIA-1 which is directed to intracellular granules within cytotoxic T-cells. Furthermore, programmed cell death of expanded T-cells could be prevented by cocultivation with fibroblasts which are believed to secrete a cytokine pattern preventing activated T-cells from apoptosis after withdrawal of IL-2 and other stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Investigations on autologous T-cells for adoptive immunotherapy of AIDS. 757 1

The HIV viral burden and RNA expression in a selected group of infected, clinically non-progressor patients were investigated. Five fast-progressor patients and 10 AIDS cases were included as controls. The HIV viral load was investigated by semiquantitative polymerase chain reaction (PCR) in adherent macrophages and in genomic and extragenomic fractions of lymphocytes. HIV DNA was not found in macrophages in the non-progressor subjects, was weakly positive in 2 of 5 fast-progressors and strongly positive in most of the AIDS patients. The number of HIV proviruses found in lymphocytes of the non-progressor subjects varied from 5 to 160 copies/microgram DNA, values ten times lower than those recorded in fast-progressors and AIDS patients. The extragenomic HIV DNA (2 LTR forms) was absent or barely detectable in the lymphocytes from non-progressors and abundant in the other groups. HIV RNA was not found in the lymphocytes of all non-progressors. This may indicate that a latent state of HIV provirus exists in the lymphocytes of these subjects. To investigate this point, cultivation and stimulation with PHA (phytohemoagglutinin) and PMA (phorbol 12-myristate 13-acetate) of lymphocytes from these subjects were attempted but after 6 days HIV RNA (RT-PCR for gag region) was still absent or barely detectable in these patients. There are no other reports of the absence of HIV provirus induction in lymphocytes from infected individuals. If confirmed in a larger number of patients, such non-inducibility might serve as a predictor marker of progression of the disease.
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PMID:Peripheral lymphocytes of clinically non-progressor patients harbor inactive and uninducible HIV proviruses. 763 97

Cytotoxic T lymphocytes (CTL) play an important role in the immune response to viral infection by recognizing and destroying infected cells. HIV-1 elicits an unusually strong CTL response in infected individuals and clearance of the viremia of acute infection coincides with the development of HIV-specific CTL. Because HIV-specific CTL may provide protection against de novo viral infection, we compared the CTL response in seronegative volunteers treated with two vaccination approaches. Seven volunteers were immunized with a live recombinant vaccinia virus expressing the HIV envelope protein gp160LAI (HIVAC-1e) and boosted with 640 micrograms recombinant baculovirus-expressed gp160LAI in alum 1-13 months later. In a second study, three volunteers underwent four successive immunizations with 640 micrograms subunit gp160LAI in alum at 0, 1, 6, and 12 months. The first vaccination strategy using a liver vector would be expected to generate gp160-specific CTL, while for the second, using only whole-protein subunit, the generation of specific CTL would be unlikely. Predominantly CD8+ T-cell lines generated from PBMC by nonspecific stimulation with PHA and IL-2 were screened after three to four weeks of culture for cytolytic activity against autologous targets infected with vaccinia vectors encoding envLAI, RT, gag, and lacZ control. A strong gp 160-specific CTL response was detected in two vaccines in the recombinant vaccinia plus subunit boost study. Modest responses were seen in four of the other five live vector-primed vaccinees. No significant gp160-specific CTL were observed in three volunteers given only subunit rgp160 or in five control subjects.
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PMID:A vaccinia-gp160-based vaccine but not a gp160 protein vaccine elicits anti-gp160 cytotoxic T lymphocytes in some HIV-1 seronegative vaccinees. 764 81

Cytokine responses are dramatically affected when HIV-1 infected cells are activated with certain antigenic stimuli. We report the effects of HIV-1 tat gene in cytokine modulation, using HIV-1 tat transfected T (Jurkat) and B (Raji) cell lines. Studying the effect of tat and/or PMA + PHA on mRNA expression of 14 cytokines (IL-1 alpha, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, TNF-alpha, TNF-beta, GM-CSF, TGF-beta, IFN-gamma and MIP-1 alpha) illustrated differential effects. In addition to the varied effects of tat on the steady state levels of cytokine mRNAs, tat induced the secretion of TNF-beta preferentially in both B and T cell lines, either by itself as in Raji B cell line or synergistically upon PMA + PHA stimulation as in Jurkat T cell line.
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PMID:Differential expression of cytokine genes in HIV-1 tat transfected T and B cell lines. 769 26

Levels of circulating immune complexes (CIC) measured by precipitation with 1.04 M ammonium sulfate ranged from 22 to 2,040 micrograms/ml in a group of 141 HIV-infected patients. CIC were elevated (> 200 micrograms/ml) in 72.2% of infected individuals. When analyzed for their HIV antigen composition, those CIC containing HIV antigens were found more frequently in patients clinically affected (68.6%) than in asymptomatic individuals (31.4%; p < 0.001). Anti-CD4 activity of 89 isolated CIC was detected in 43.8% of these patients, but only in 7.6% of the cases these CIC could bind to native CD4+ molecules. CIC with anti-CD4 activity could inhibit PHA stimulation of normal peripheral blood lymphocytes. Anti-CD4 activity in CIC was independent of the clinical and immunological status of HIV-infected patients.
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PMID:Anti-CD4 activity in circulating immune complexes in HIV-infected patients. 771 54

Arachidonic acid (AA) has been shown to interact with transmembrane signaling pathways involved in T-cell activation. The latter have been shown to be impaired in lymphocytes obtained from HIV-infected patients. In the present study, AA and its metabolite, PGE2, released from differentiating human mononuclear phagocytes in response to HIV infection, and their relationship to HIV replication and TNF-alpha production were examined. The macrophage (M phi) cultures were more permissive for HIV replication than monocyte (MO) cultures. AA release in response to HIV infection was observed in both MO and M phi with a peak at 24 hr postinfection (p.i.). This AA release was 3.8- and 6-fold that of uninfected MO and M phi cultures, respectively. Supernatants from MO and M phi cultures at the peak of AA production inhibited [3H]thymidine uptake of peripheral blood mononuclear cells in response to PHA by 45 and 54%. At 24 hr p.i., PGE2 production was increased in both MO and M phi cultures. This increase was associated with a 1.2- and 20-fold inhibition of IL-1 production, respectively. TNF release, however, increased through day 14 p.i. Treating mock-infected MO with recombinant TNF-alpha induced AA release. Monoclonal antibodies to TNF inhibited this release by 80%. TNF (0.01-0.4 microgram/ml) added exogenously to MO produced a biphasic pattern of AA release; while low concentrations were stimulatory, higher concentrations were inhibitory. Treating monocyte and macrophage cultures with mAb to TNF-alpha inhibited the HIV-induced release of AA and PGE2. These findings indicate that HIV-induced TNF-alpha regulates the release of AA and PGE2, which might provide insight into the mechanisms involved in the pathogenesis of HIV-related disorders.
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PMID:HIV-induced TNF-alpha regulates arachidonic acid and PGE2 release from HIV-infected mononuclear phagocytes. 774 31

In contrast to the purely enhancer-dependent effect of cytokines such as TNF on the activity of the HIV regulatory region (LTR), we observed that okadaic acid (OKA) activates HIV transcription through both the enhancer, responding to the factor NF-kappa B, and the promoter domain of the LTR. The inducibility of HIV LTR-driven luciferase expression constructs in lymphoblastoid cells stimulated by OKA depended on both functional Sp1 binding elements and the ability of the TATA box to bind the protein TBP. In both transformed and normal lymphocytes, OKA stimulation induced intense phosphorylation of the constitutively expressed Sp1 protein in the nucleus, a property of OKA not shared by TNF, phorbol ester, or PHA and interleukin 2. Responsiveness of LTR constructs deleted of kappa B elements to HIV Tat expression was increased upon OKA but not TNF stimulation. Our results suggest that SP1 phosphorylation induced by OKA, a selective inhibitor of the serine-threonine phosphatase PP2A, facilitates the formation of a transcription complex involving general transcription factors, HIV Tat, and Sp1 proteins. The formation of this complex would increase, independently of an in synergy with NF-kappa B, the low basal activity of the HIV LTR observed in normal T lymphocytes.
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PMID:Induction of Sp1 phosphorylation and NF-kappa B-independent HIV promoter domain activity in T lymphocytes stimulated by okadaic acid. 774 47


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