Human Immunodeficiency virus-I Research Articles

Metal-Enhanced Aggregation-Induced Emission Strategy for the HIV-I RNA-Binding Ligand Assay.

The HIV-Ι trans-activation responsive (TAR) RNA-trans-activator of transcription (Tat) protein complex is crucial for the efficient transcription of the integrated human immunodeficiency virus-I genome and is an established therapeutic target for AIDS diagnosis and treatment. Developing a sensitive strategy for the TAR RNA-binding ligand assay could provide antiviral leads with a radically new mechanism for the treatment of AIDS. Herein, a new TAR RNA-binding ligand assay platform was established using a signal amplification strategy that combines aggregation-induced emission (AIE) with a metal-enhanced fluorescence (MEF) concept. The tetraphenylethylene (TPE) derivative was labeled on the Tat peptide as a fluorescent molecule, while the TAR RNA was immobilized on the surface of the Fe3O4@Au@Ag@SiO2 nanoparticles (NPs) to specifically bind the TPE-Tat peptide. The TPE-Tat peptide was weakly emissive itself while emitting strongly in the NP-TAR-TPE-Tat complex by the AIE and MEF signal amplification effect. It was confirmed by known Tat peptide competitors that this system could be applied to the screening and detection of TAR RNA-binding ligands because they could replace the TPE-Tat peptide from the complex and make the system fluorescence decrease. When this system was adopted to test four candidate ligands, it was found that bisantrene had a favorable TAR RNA-binding ability. The proposed AIE-MEF strategy not only provides a sensitive and reliable method for the TAR RNA-binding ligand assay but also can avoid the influence of ligands on fluorescent detection in the conventional displacement assay.

Endemic and Indigenous Plants from Mascarene Islands with Antiviral Propensities.

Antiviral resistance and inefficiency of available antiviral drugs to effectively treat viral infections have prompted many researchers worldwide to explore medicinal plants and their isolated compounds as alternative antivirals. The rich flora from the Mascarene Islands has also been thoroughly studied for their wide therapeutic activities, including their antiviral properties. The aim of this review is to highlight the antiviral propensities of Mascarene endemic and indigenous medicinal plants. A review of the literature was conducted via major databases and other primary sources of information. The inhibitory concentration/effective dose causing 50% viral inhibition (IC50/ED50), cytotoxic concentration causing 50% reduction in cell viability (CC50), and selectivity index (SI) were reported, and mechanisms of antiviral action were also discussed. Stillingia lineata was the most effective against chikungunya virus (SI: 10.9), and among its isolated compounds, 12-O-acetylphorbol-13(2″-methyl)- butyrate and 12-deoxyphorbol- 13(2″-methyl)butyrate were the most potent and selective inhibitors of chikungunya virus replication (SI: 41 and >240, respectively). 12-O-acetylphorbol-13(2″-methyl)- butyrate, 12β-O-[nona- 2Z,4E,6E-trienoyl]-4α-deoxyphorbol-13-butyrate, 12-deoxyphorbol-13(2″-methyl)butyrate, and 12-deoxyphorbol-13-[8'-oxohexadeca-2E,4E,6E-trienoate showed strong selective antiviral effect on human immunodeficiency virus-I (SI: 36-899) and II (SI: 33-2056). Obetia ficifolia and Erythroxylon laurifolium were most active against the herpes virus (SI: 18.5 and 16, respectively). Labourdonnaisia glauca showed potent anti-poliovirus activity (SI: 40), while Badula insularis, Labourdonnaisia glauca and Myonima violacea were active against rhinovirus (SI: 1.3-2.5). Both anti-zika and anti-dengue virus activities were reported for Aphloia theiformis, Doratoxylon apetalum, Phyllanthus phillyreifolius and Psiloxylon mauritianum. Promising spectrum of antiviral properties notably against zika, dengue, chikungunya, polio-, rhino-, herpes, and human immunodeficiency viruses were presented by the Mascarene plants suggesting them as viable candidates for the potential development of effective natural antiviral drugs.

SPECTROPHOTOMETRIC METHOD DEVELOPMENT AND VALIDATION FOR SIMULTANEOUS ESTIMATION OF ABACAVIR AND LAMIVUDINE IN COMBINED DOSAGE FORM

Antiretroviral therapy [ART] has been developed remarkably within last three decades, since the first NRTI (nucleoside reverse transcriptase inhibitor) developed. For the mostly patients the challenge of complete and sustain suppression of viral has been clarify, since the triple therapy arrived. Convenient pill burden and tolerability are the main limiting factor for enhancing the long term benefit of ART. ABACAVIR (ABA) and LAMIVUDINE (LAM) are synthetic nucleotide analog (SNA) that showing a synergistic and potent inhibitory effect on human immunodeficiency virus-I (HIV-I), causative agent of AIDS. ABA and LAM belongs to nucleoside reverse transcriptase inhibitor (NRTI) class. As per new therapeutic strategy these two antiretroviral (ARV) drugs are required for the treatment of AIDS. When ARV regimens changed due to lack to virologic response ABA should be avoided. ABA is getting converted in to the active metabolite (carbovir triphosphate) which is an deoxyguanosine-5’ triphosphate analog by intracellular enzymes. LAM gets converted in its active 5’-triphosphate metabolite through phosphorylation. Chemically, ABA is (1S, cis)-4-[2-amino-6-(cyclopropyl amino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulphate and LAM is (2R, cis)-4-amino-1-(2-hydroxymethyl-1, 3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Fig. 1 and 2 show ABA and LAM’s structure respectively.

Vibrational Analysis and Molecular Docking Studies on some Ribonuclease-H HIV Inhibitors

Ribonuclease-H (RNase-H) enzyme of the human immunodeficiency virus (HIV) reverse transcriptase (RT) shows inhibitory activity with novel galloyl derivatives having enzymatic assays of IC50 S at sub to low micromolar concentration. The computational analysis of these stated galloyl derivatives was carried out in order to extract information and performance with the target proteins. The compounds N-hydroxylisoquinolinediones (HID), β-thujaplicinol, diketoacid, diketoacid ester, pyrimidinol carboxylic acids, naphthyridinones, 3hydroxypyrimidine-2,4-dione (HPD), and hydroxypyridonecarboxylic acids are the selected galloyl derivatives of human immunodeficiency virus-I (HIV-I) RNase-H active site inhibitors that were optimized using Turbomole software. Further evaluation of their NMR shielding of the stated compounds was performed using B3-LYP hybrid functional, and the def-SV basis set was carried out from the same software. These optimized compounds were then docked to targets (PDB Id: 5EGA and 3K2P) using AutoDock 4 software. After analyzing the docking result, Hydroxylisoquinoline and Naphthyridinones give better binding results with both the targets.

Prevention of infection-related cancers in the WHO Western Pacific Region.

A considerable number of infectious agents have been classified as human carcinogens Group 1 by the International Agency for Research on Cancer. Major infection-related cancers such as cancers of nasopharynx (53%), stomach (60%) and liver (63%) occur in the World Health Organization Western Pacific Region. Many infection-related cancers are preventable, particularly those associated with human papilloma virus, Helicobacter pylori, human immunodeficiency virus-I, hepatitis B virus and hepatitis C virus and liver flukes. Mongolia shows the highest prevalence of hepatitis B virus and hepatitis C virus, and China shows the highest prevalence of Helicobacter pylori. Chronic infection is attributable for 17-28% of overall cancer incidence or mortality in China, Japan and Korea. Through infant immunization for hepatitis B, 30 of 37 countries and areas in the Western Pacific Region have reached the 2012 milestone of chronic hepatitis B virus infection prevalence of <2% in 5-year-old children and countries and areas of the region are now striving toward reaching the regional goal of <1% by 2017. Human papilloma virus immunization program is implemented either by government funding or, in some low-income countries, by public and private sector organizations. Cervical cancer screening via visual inspection with acetic acid or Pap smear is available in many Western Pacific Region Member States. More efforts are needed to implement new World Health Organization guide to vaccinate 9- to 13-year-old girls with two doses of human papilloma virus vaccine, and use human papilloma virus tests to screen women to prevent and control cervical cancer including guaranteed monitoring and appropriate follow-up for abnormal results.

Fluorometric assay for phenotypic differentiation of drug-resistant HIV mutants.

Convenient drug-resistance testing of viral mutants is indispensable to effective treatment of viral infection. We developed a novel fluorometric assay for phenotypic differentiation of drug-resistant mutants of human immunodeficiency virus-I protease (HIV-PR) which uses enzymatic and peptide-specific fluorescence (FL) reactions and high-performance liquid chromatography (HPLC) of three HIV-PR substrates. This assay protocol enables use of non-purified enzyme sources and multiple substrates for the enzymatic reaction. In this study, susceptibility of HIV mutations to drugs was evaluated by selective formation of three FL products after the enzymatic HIV-PR reaction. This proof-of-concept study indicates that the present HPLC-FL method could be an alternative to current phenotypic assays for the evaluation of HIV drug resistance.

Hepatitis C Virus and Human Immunodeficiency Virus-I (HIV) Co-Infection in Children in Benin City, Nigeria.

The study was done to assess the incidence of Hepatitis C virus (HCV) infection and co — infection with Human Immunodeficiency virus - 1 (HIV) amongst children between the ages of 0 — 17 years in Benin City, Nigeria. Blood samples were collected from four hundred (400) children selected from public and private hospitals as well as primary and secondary schools in Benin City. Samples were analyzed for HCV using the One step Hepatitis C virus strip. HIV analysis was done using HIV rapid testing algorithm. Two hundred (200) out of the four hundred (400) children were randomly screened for Hepatitis B virus (HBV) infection using the Clinotech diagnostic HBsAg detection test. Questionnaires were used to obtain information about the children. Of all the children, only one child tested positive to HCV infection, giving a prevalence rate of 0.25%. All screening for HBV was negative. The child with HCV (a female) also tested positive for HIV, suggestive of a co — infection. There was no obvious influence of previous blood transfusion, exposure to intramuscular injections, place of delivery or educational status of the children’s parents on the results obtained. Keywords : Hepatitis C virus, HIV, Children.

Bioactive Compounds of Colostrum and Its Application

Colostrum is the initial milk secreted by bovine during parturition and the first few days after birth. Colostrum is a gift of nature used to protect the newborn’s immune system and provides passive immunity against pathogens. The presence of bioactive components such as insulin-like growth factor I and II (IGF-I and IGF-II), lactoferrin, lysozyme, lactoperoxidase, and immunoglobulin make the colostrum active against pathogens such as Escherichia coli, Salmonella typhimurium, Shigella dysenteria, Listeria monocytogens, Streptococcus mutans, Bacillus stearothermophilus, and Bacillus subtilis. It is also active against Herpes simple virus type-I (HSV-I), Human Immuno-deficiency virus-I (HIV-I), and human cytomegalovirus. Lysozyme is an antibacterial and lytic enzyme; whereas lactoperoxidase is a major antibacterial found in colostrum; it is toxic to gram-positive and gram-negative bacteria. Lactoperoxidase inactivates the polio virus, vaccinia, and human immunodeficiency virus type-I in-vitro. Immunoglobulins are considered an important bioactive component in colostrum, and it contains high levels of immunoglobulin G (Ig G). Immunosupplementation with bovine milk antibodies has been shown to provide local protection to the gastrointestinal tract against disease. The restricted technical and hygienic problems, along with the unstable physio-chemical nature of colostrum, has resulted in minimal utilization of colostrum on Industrial scale.

Selective depletion of CD56(dim) NK cell subsets and maintenance of CD56(bright) NK cells in treatment-naive HIV-1-seropositive individuals.

Human immunodeficiency virus-I (HIV-1) infected patients show a gradual loss of natural killer (NK) cells that correlates with disease progression. However, the effect of HIV-1 infection on different NK cell subsets has not been fully characterized. In healthy individuals most NK cells are CD3-CD56+ and two different subpopulations, CD56(dim) and CD56(bright), can be distinguished by the mean fluorescence intensity. Although it was originally suggested that CD56(bright) NK cells represent the precursors of the CD56dim subpopulation, recent cumulative data indicate that CD56(bright) and CD56(dim) NK cells are phenotypically, functionally, and developmentally different NK cell subsets. In this study, the analysis of CD56(bright) and CD56(dim) NK subsets showed that neither the number nor the phenotype of CD56(bright) NK cells were significantly altered in treatment-naive HIV-1-infected individuals, whereas the number of CD56(dim) NK cells was decreased. We also have studied NK cell subsets defined by the expression of CD56 in combination with CD16, CD161, or CD94 molecules. Our results demonstrated a preferential decrease of CD3-CD56+ NK cells coexpressing CD16 and CD161 but lacking CD94 molecules. On the contrary an increased percentage of NK cells that do not express CD56 molecules but express CD16, CD161, or CD94 was also found in HIV-1-infected individuals. As it has been proposed that these CD56-negative NK cells expressing other NK cell receptors represent immature NK cells with low cytolytic capacity, our results support that a defective differentiation from immature CD56 negative NK cells to mature CD56(dim) NK cells occurs in HIV-1 infection.

Aggregation of polyA–HIV-1 nucleocapsid protein NCp7 complexes and properties of the aggregates

We have previously shown that in solution, depending on solute and solution conditions, an ordered aggregation of polyA–NCp7 complexes takes place. The kinetic behaviour of the polyA(homoribopolynucleotide)–NCp7(human immunodeficiency virus-I nucleocapsid protein) aggregating system was studied at physiological NaCl concentration (150 mM) using quasielastic light scattering measurements. The kinetic curves were fitted to a power law equation. For the aggregate size growth with time at initial concentrations of NCp7=0.3 μM and nucleotide-to-protein molar ratios of 17 and 50 we obtained for power exponents of 0.15 and 0.23, respectively. On the basis of the aggregate size at which maxima are observed on the light scattering versus time curves we suggested a method for determining the mechanism of aggregation. Thus we found that in the process of polya–NCp7 aggregation, the growth proceeds by fusion of commensurable in size aggregates. The aggregate size dependence on NCp7 concentration showed critical behaviour. The calculated parameters of the power law (rate of growth n and a, related to the aggregate properties) showed in the critical region (0.2–0.3 μM NCp7) a marked change. Electro-optic measurements (electric birefringence and electric light scattering) gave no evidence for the existence of optically anisotropic and/or anisodiametric suspended aggregates under the experimental conditions accessible for the electro-optic instruments used. Quasielastic light scattering and electron microscopy studies showed that at all stages of aggregate growth, under a broad range of experimental conditions, the aggregates were spherical with a unimodal, relatively narrow size distribution. We consider that combining the method suggested by us for studying the mechanism of aggregation with electro-optic and electron microscopy studies might be helpful for modelling the HIV-1 nucleocapsid (composed of genomic RNA–NCp7 complexes) assembly as well as transfectious particles for gene transfer (vectors) or non-infectious particles as candidate vaccines.

The potential roles of endogenous retroviruses in autoimmunity.

Endogenous retroviruses (ERVs) are estimated to comprise up to 1% of human DNA. While the genome of many ERVs is interrupted by termination codons, deletions or frame shift mutations, some ERVs are transcriptionally active and recent studies reveal protein expression or particle formation by human ERVs. ERVs have been implicated as aetiological agents of autoimmune disease, because of their structural and sequence similarities to exogenous retroviruses associated with immune dysregulation and their tissue-specific or differentiation-dependent expression. In fact, retrovirus-like particles distinct from those of known exogenous retroviruses and immune responses to ERV proteins have been observed in autoimmune disease. Quantitatively or structurally aberrant expression of normally cryptic ERVs, induced by environmental or endogenous factors, could initiate autoimmunity through direct or indirect mechanisms. ERVs may lead to immune dysregulation as insertional mutagens or cis-regulatory elements of cellular genes involved in immune function. ERVs may also encode elements like tax in human T-lymphotrophic virus type I (HTLV-I) or tat in human immunodeficiency virus-I (HIV-I) that are capable of transactivating cellular genes. More directly, human ERV gene products themselves may be immunologically active, by analogy with the superantigen activity in the long terminal repeat (LTR) of mouse mammary tumour viruses (MMTV) and the non-specific immunosuppressive activity in mammalian type C retrovirus env protein. Alternatively, increased expression of an ERV protein, or expression of a novel ERV protein not expressed in the thymus during acquisition of immune tolerance, may lead to its perception as a neoantigen. Paraneoplastic syndromes raise the possibility that novel ERV-encoded epitopes expressed by a tumour elicit immunity to cross-reactive epitopes in normal tissues. Recombination events between different but related ERVs, to whose products the host is immunologically tolerant, may also generate new antigenic determinants. Frequently reported humoral immunity to exogenous retrovirus proteins in autoimmune disease could be elicited by cross-reactive ERV proteins. A review of the evidence implicating ERVs in immune dysfunction leads to the conclusion that direct molecular studies are likely to establish a pathogenic role for ERVs in autoimmune disease.

HIVgp120 activates autoreactive CD4-specific T cell responses by unveiling of hidden CD4 peptides during processing.

T cells are made tolerant only to those self-peptides that are presented in sufficient amounts by antigen-presenting cells. They ignore cryptic self-determinants, such as either those not generated by processing machinery or generated in insufficient amounts. It is anticipated that mechanisms that either change antigen processing or increase the yield of previously "invisible" peptides may be capable of inducing T cell priming and, if they are self-maintained, may sustain autoimmune diseases. Herein, we demonstrate for the first time a mechanism by which the gp120 human immunodeficiency virus-I, by downregulating plasma membrane CD4 and increasing its processing, unveils hidden CD4 epitopes, inducing an autoimmune-specific T cell response.

Biochemical mechanism of HIV-I Vpr function. Specific interaction with a cellular protein.

vpr is an accessory gene of human immunodeficiency virus I (HIV-I). Although unnecessary for viral replication in T cell lines, growing evidence suggests that it is essential for virus replication in monocytes/macrophages and for replication in vivo. We expressed HIV-I vpr in Escherichia coli and purified Vpr by affinity chromatography. In a coprecipitation assay, the purified Vpr interacted specifically with a cellular protein designated as Vpr-interacting protein, or RIP. Mutational analysis suggested that this interaction required a domain rich in leucine/isoleucine residues and highly conserved between HIV-I and SIVmac Vprs. During transient expression in mammalian cells, HIV-I Vpr was localized in the nucleus. However, mutational analysis failed to identify in Vpr a typical nuclear localization signal rich in basic amino acid residues. Instead, Vpr nuclear localization seemed to correlate with Vpr interaction with RIP. Mutations in the C-terminal 20-amino acid region containing a cryptic nuclear localization signal did not abolish Vpr nuclear localization or interaction with RIP, whereas point mutations in the leucine/isoleucine-rich domain abolished Vpr interaction with RIP and rendered Vpr unstable during transient expression. These results suggest that RIP may be involved in Vpr function.

Novel Family of Gynecologic Cancer Antigens Detected by Anti-HIV Antibody

Objective: The reactivity of gynecologic cancer proteins with monoclonal antibody (MAb) directed against the human immunodeficiency virus I (HIV-I) was tested. Methods: Cytoplasmic and nuclear proteins, extracted from a broad range of gynecologic cancers obtained during standard surgical procedures, were tested in Western blotting with MAb 5023 developed against the amino acid sequences 308–322 of the envelope protein gp120 of HIV-I. Results: Three cell membrane proteins, Mrl20,000 (p120), Mr41,000 (p41), and Mr24,000 (p24), and one chromatin protein, Mr24,000 (p24), were detected by MAb 5023 in invasive, poorly differentiated cervical squamous-cell carcinoma; ovarian serous cystadenocarcinoma; poorly and well-differentiated endometrial carcinoma; vulvar squamous-cell carcinoma; and malignant mixed müllerian tumor. The same antigens were identified in cervical carcinoma cell line SiHa. Neither p120 nor p24 was recognized by other MAbs directed against the variable loop of gp120. Antigens p120 and p41 were undetectable in normal ovarian tissue and in biopsy samples of normal vaginal and rectal mucosa. Rectosigmoid cancer as well as colon carcinoma, lung carcinoma, and melanoma cell lines all tested negative. Conclusions: The identified antigens may represent either the products of human genes (proto-onc-ogenes) or, more likely, the products of an unknown virus specifically expressed in female cancer.

Synthesis of myristic acid analogs with anti-HIV activity that may be resistant to metabolic processing by β-oxidation

Novel classes of oxatetradecanoic acid analogs 10, 11, 13, 16, and 21 were synthesized as alternative substrates for myristoylCoA:protein N-myristoyltransferase. These compounds inhibit replication of human immunodeficiency virus I (HIV-I) in acutely infected CD4-positive human T lymphocyte cell lines. The antiviral activity and potential metabolic stability of these compounds may make attractive therapeutic agents.

4-oxatetradecanoic acid is fungicidal for Cryptococcus neoformans and inhibits replication of human immunodeficiency virus I.

Candida albicans and Cryptococcus neoformans are major causes of systemic fungal infections, particularly in patients with acquired immunodeficiency syndrome. Metabolic labeling studies revealed that these organisms synthesize a small number of N-myristoylproteins, the most prominent being 20-kDa ADP-ribosylation factors (Arfs). C. albicans Arf has approximately 80% identity with the essential Arf1 and Arf2 proteins of Saccharomyces cerevisiae. [3H]Myristic acid analogs with oxygen for -CH2- substitutions at C4, C6, C11, and C13 are incorporated into cellular N-myristoylproteins, phospholipids, and neutral lipids produced by these three yeasts during exponential growth at 30 degrees C in complex media. Analog- and organism-specific differences in the efficiency of labeling of proteins and lipid classes were observed. The effects of oxatetradecanoic acids with oxygen for -CH2- substitutions at C3-C13 on C. neoformans, C. albicans, and S. cerevisiae were assessed during mid-log phase growth at 30 degrees C. A single dose of 3-oxa-, 4-oxa-, 5-oxa- or 6-oxatetradecanoic acid (O3-O6, final concentration = 300 microM) was able to inhibit growth of C. neoformans in the order O4 greater than O5 greater than O3 approximately O6. The other compounds were inactive. 4-Oxatetradecanoic acid was fungicidal, producing a 10,000-fold reduction in viable cell number 1 h after administration and continued suppression of cell growth for 7 h. A clear dose response was observed over a concentration range of 100-300 microM. 4-Oxatridecanoic acid was 100-fold less potent in reducing cell viability than 4-oxatetradecanoic acid but more potent than 5-oxatridecanoic acid. O4 produced approximately 10-100-fold reductions in the viability of C. albicans and S. cerevisiae at 300-500 microM, respectively, whereas O5 and O6 were less active. Since N-myristoylation of the Pr55gag polyprotein precursor produced by human immunodeficiency virus I (HIV-I) is essential for its assembly, we also assessed the antiviral effects of 4-oxatetradecanoic acid. O4 is able to produce a 50% reduction in the replication of HIV-I in acutely infected human T-lymphocyte cell lines at a concentration of 18 microM. Together, these data suggest that (i) the position of the oxygen for methylene substitution is a critical determinant of the fungicidal activity of O4 and (ii) NMT may be an attractive therapeutic target for treating opportunistic fungal infections in patients infected with HIV-I.

Substrate specificity of Saccharomyces cerevisiae myristoyl-CoA: protein N-myristoyltransferase. Analysis of fatty acid analogs containing carbonyl groups, nitrogen heteroatoms, and nitrogen heterocycles in an in vitro enzyme assay and subsequent identification of inhibitors of human immunodeficiency virus I replication.

Covalent attachment of myristic acid (C14:0) to the amino-terminal glycine residue of a variety of eukaryotic cellular and viral proteins can have a profound influence on their biological properties. The enzyme that catalyzes this modification, myristoyl-CoA-protein N-myristoyltransferase (NMT), has been identified as a potential target for antiviral and antifungal therapy. Its reaction mechanism is ordered Bi Bi with myristoyl-CoA binding occurring before binding of peptide and CoA release preceding release of myristoylpeptide. Perturbations in the binding of its acyl-CoA substrate would therefore be expected to have an important influence on catalysis. We have synthesized 56 analogs of myristic acid (C14:0) to further characterize the acyl-CoA binding site of Saccharomyces cerevisiae NMT. The activity of fatty acid analogs was assessed using a coupled in vitro assay system that employed the reportedly nonspecific Pseudomonas acyl-CoA synthetase, purified S. cerevisiae NMT, and octapeptide substrates derived from residues 2-9 of the catalytic subunit of cyclic AMP-dependent protein kinase and the Pr55gag polyprotein precursor of human immunodeficiency virus I (HIV-I). Analysis of ketocarbonyl-, ester-, and amide-containing myristic acid analogs (the latter in two isomeric arrangements, the acylamino acid (-CO-NH-) and the amide (-NH-CO)) indicated that the enzyme's binding site is able to accommodate a dipolar protrusion from C4 through C13. This includes the region of the acyl chain occurring near C5-C6 (numbered from carboxyl) that appears to be bound in a bent conformation of 140-150 degrees. The activities of NMT's acyl-CoA substrates decrease with increasing polarity. This relationship was particularly apparent from an analysis of a series of analogs in which the hydrocarbon chain was terminated by (i) an azido group or (ii) one of three nitrogen heterocycles (imidazole, triazole, and tetrazole) alkylated at either nitrogen or carbon. This inverse relationship between polarity and activity was confirmed after comparison of the activities of the closely related ester- or amide-containing tetradecanoyl-CoA derivatives. Members from all of the analog series were surveyed to determine whether they could inhibit replication of human immunodeficiency virus I (HIV-I), a retrovirus that depends upon N-myristoylation of its Pr55gag for propagation. 12-Azidododecanoic acid was the most active analog tested, producing a 60-90% inhibition of viral production in both acutely and chronically infected T-lymphocyte cell lines at a concentration of 10-50 microM without associated cellular toxicity.

Kaposi's sarcoma of the parotid gland in acquired immunodeficiency syndrome

A patient with acquired immunodeficiency syndrome complained of a dry mouth and bilateral swelling of the parotid glands. Kaposi's sarcoma (KS) was found within the tissue of the parotid gland. Although KS is a common manifestation of acquired immunodeficiency syndrome, the presence of KS in the salivary glands is very rare. The human immunodeficiency virus I (HIV-I) genome was not identified in parotid glandular cells or in KS cells in this case, although the virus was detected in infiltrating lymphocytes and in tissue macrophages.

Detection of high levels of immunoreactive human beta-1 interferon in sera from HIV-infected patients

We have examined human interferon beta-1 (HuIFN-β1) levels in the sera from patients with various diseases by using a newly developed highly sensitive enzymelinked immunosorbent assay system (ELISA). High levels of HuIFN-β1 were detected in the sera from Human Immunodeficiency Virus-I (HIV-I) infected patients, especially of asymptomatic carriers. The serum level of HuIFN-β1 may be a good indicator of HIV-I infection and of other immunological disorders.

Cultured, AIDS-related Kaposi's sarcoma cells express endothelial cell markers and are weakly malignant in vitro.

Up to 30% of patients with acquired immunodeficiency syndrome (AIDS) suffer from Kaposi's sarcoma (AIDS-KS). The histogenesis and neoplastic nature of this tumor is still controversial. We have established cell cultures of KS biopsies from 7 patients with AIDS. All donors were seropositive for the human immunodeficiency virus I (HIV-I), cytomegalovirus (CMV) and hepatitis B virus (HBV). The tumors were histologically shown to be KS. Cell cultures derived from these tumors all expressed the endothelial cell marker BMA 120 antigen. Most of these cultures were positive for acetylated low-density lipoprotein (acLDL) uptake and alkaline phosphatase (AP) expression, and negative for factor-VIII-related antigen (FVIII-RAg). The staining pattern was heterogeneous with respect to number of endothelial cell markers expressed in each culture. We conclude from subcloning experiments that the cultured cells cease to express acLDL receptor and AP, but not the antigen detected by the monoclonal antibody (MAb) BMA 120. The cells grew well in culture up to 50 passages and showed a fibroblast-like morphology. Assays performed to investigate their degree of malignancy revealed a significantly increased passage number under reduced serum conditions as compared to normal fibroblasts but no tumor formation in nude mice. Neither HIV, HBV nor CMV sequences were found in any of the cell lines tested. We conclude that AIDS-KS is an endothelial-cell-derived neoplasm of low malignancy and that HIV, HBV and CMV are not directly involved in its genesis.