Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A stable cell line encoding the sequences of all the human immunodeficiency virus type 1 proteins, with the exception of the gp160 envelope glycoprotein, was derived from transfection of monkey COS-7 cells. This cell line, referred to as CH-1, produces active viral protease that correctly processes its natural substrates and yields capsid particles. These particles contain reverse transcriptase activity and packaged viral RNA but are noninfectious. The level of expression of viral proteins is not toxic to the cells, yet it is comparable to that observed for chronically infected lymphocytes. These constitutively synthesized viral proteins provide a consistent system for the analysis of potential inhibitors of late viral functions. The lack of gp160 increases the biosafety of this assay system, while it allows the measurement of the effects on the production and release of capsid particles. A human immunodeficiency virus type 1 protease inhibitor was used to confirm the viral polyprotein maturation pathway in this system. Particles from cells treated with this protease inhibitor contain unprocessed p55gag precursor and have the same density as the mature particles. These immature particles contain viral RNA, but reverse transcriptase activity is significantly reduced. This cell line may serve to identify compounds that are able to affect viral assembly and maturation as well as to identify the interactions between the viral and cellular proteins involved in these essential processes.
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PMID:Constitutive production of nonenveloped human immunodeficiency virus type 1 particles by a mammalian cell line and effects of a protease inhibitor on particle maturation. 784 May 83

Since plasma protein binding of antiinfectives can adversely affect drug activity, the effect of serum proteins on the in vitro antiviral activity of A77003, a human immunodeficiency virus type 1 (HIV) protease inhibitor, was investigated. In vitro, A77003 is effective in both acute and chronic infection in 10% fetal bovine or human serum. As the concentration of human serum was increased to 50%, antiviral efficacy decreased 3- to 6-fold. Purified human alpha 1 acid glycoprotein (alpha 1-AGP) at physiologic concentrations (0.5-2 mg/mL) dose-dependently reduced the antiviral activity of A77003. alpha 1-AGP at 1 mg/mL also antagonized the anti-HIV activity of A77003-zidovudine combinations. Therefore, higher concentrations of HIV protease inhibitors than would be predicted, on the basis of in vitro activity in the absence of physiologic concentrations of binding protein, may be required to effectively limit viral replication in vivo.
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PMID:Reduction of the in vitro activity of A77003, an inhibitor of human immunodeficiency virus protease, by human serum alpha 1 acid glycoprotein. 787 99

Development of viral resistance to the aminodiol human immunodeficiency virus (HIV) protease inhibitor BMS 186,318 was studied by serial passage of HIV type 1 RF in MT-2 cells in the presence of increasing concentrations of compound. After 11 passages, an HIV variant that showed a 15-fold increase in 50% effective dose emerged. This HIV variant displays low-level cross-resistance to the C2 symmetric inhibitor A-77003 but remains sensitive to the protease inhibitors Ro 31-8959 and SC52151. Genetic analysis of the protease gene from a drug-resistant variant revealed an Ala-to-Thr change at amino acid residue 71 (A71T) and a Val-to-Ala change at residue 82 (V82A). To determine the effects of these mutations on protease and virus drug susceptibility, recombinant protease and proviral HIV type 1 clones containing the single mutations A71T and V82A or double mutation A71T/V82A were constructed. Subsequent drug sensitivity assays on the mutant proteases and viruses indicated that the V82A substitution was responsible for most of the resistance observed. Further genotypic analysis of the protease genes from earlier passages of virus indicated that the A71T mutation emerged prior to the V82A change. Finally, the level of resistance did not increase following continued passage in increasing concentrations of drug, and the resistant virus retained its drug susceptibility phenotype 34 days after drug withdrawal.
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PMID:Characterization of a human immunodeficiency virus type 1 variant with reduced sensitivity to an aminodiol protease inhibitor. 788 62

One of the hallmarks of human immunodeficiency virus type 1 (HIV-1) infection is the decline in CD4+ T lymphocytes which precedes the progression from an asymptomatic state to AIDS. Apoptosis (programmed cell death) is one of the mechanisms proposed to mediate this depletion. Infectious and inactivated preparations of HIV-1LAI were compared for their potential to induce apoptosis. Analysis with fluorescence-activated cell sorting using the DNA intercalative compound propidium iodide demonstrated that apoptosis occurred only with infectious HIV-1, implying that cell surface binding and signalling by the virus alone were insufficient to trigger apoptosis. Apoptosis was further confirmed by the presence of characteristic digestion of host cell DNA and morphologically by nuclear condensation observed by transmission electron microscopy. HIV infection of CD4+ T cell lines generated an accumulation of the cells in G2/M phase of the cell cycle and cells undergoing apoptosis appeared to originate from the pool of cells in the G1 phase. Inhibitors of HIV replication were used to identify the point in the virus replicative cycle at which apoptosis is induced. The reverse transcriptase inhibitor, ddI, or the HIV protease inhibitor, RO31-8959 (Saquinavir), were added either 2 h before or 6 h after HIV inoculation. Only ddI inhibited HIV-induced apoptosis when added before inoculation; however, neither treatment was effective in preventing HIV-induced apoptosis when applied 6 h after inoculation. These data indicate that apoptosis requires a single round of reverse transcription and the expression of virion proteins, but not the maturation of progeny virions. Two agents which compete with HIV for binding to CD4+ T cells, dextran sulphate and the anti-CD4 MAb Leu3a, were effective at preventing apoptosis when added 6 h after infection, implying that a subsequent gp120-CD4 interaction at the surface of an infected cell was required to complete the apoptotic process.
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PMID:Productive infection and subsequent interaction of CD4-gp120 at the cellular membrane is required for HIV-induced apoptosis of CD4+ T cells. 789 56

The aspartyl protease of the human immunodeficiency virus (HIV) is an important target for chemotherapeutic intervention because of its key role in cleaving the HIV gag-pol polyprotein during viral assembly and budding. Short peptides and peptidomimetics, which bind to the active site of the HIV aspartyl protease and inhibit processing of the polyprotein, have been synthesized. These compounds are active against HIV in vitro, but many face substantial development problems because of their rapid elimination from the body in bile and urine. Refinement of these agents appears to be necessary if they are to become useful clinically. Recently, we developed a novel chemical strategy for increasing plasma levels of HIV protease inhibitory peptides, which involves the attachment of a biodegradable phospholipid group to the C-terminus of a pentapeptide, iBOC-[L-Phe]-[D-beta-Nal]-Pip-[alpha-(OH)-Leu]-Val (7194). We coupled phosphatidylethanolamine to the C-terminal valine of 7194 to make a phospholipid prodrug (7196). In vitro assays in HT4-6C cells infected with HIV-1 showed that the antiviral activity of the C-terminal phospholipid prodrug, 7196, was equal to that of the free peptide, 7194. Similar results were obtained in vitro when a related pentapeptide (7140) was derivatized at the N-terminal with dipalmitoylphosphatidylethanolamine-succinic acid (7172). Tritium-labeled 7194 and 7196 were prepared and injected intravenously into rats at 3 mumol/kg; then the plasma was assayed for native compound and metabolites by HPLC radioactivity flow detection. The peak plasma level of the tritium-labeled lipid prodrug (7196) was 36 microM versus 1.6 microM for the free protease inhibitor pentapeptide (7194). The area under the curve of the phospholipid prodrug (7196) was 48-fold greater and its mean residence time was increased 43-fold versus the free peptide (7194). Phospholipid prodrugs appear to offer an alternative approach to optimizing in vivo performance of HIV protease inhibitors and other small peptides.
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PMID:Phospholipid prodrug inhibitors of the HIV protease. Antiviral activity and pharmacokinetics in rats. 794 39

KNI-272 represents a peptide-based protease inhibitor having potent antiretroviral activity against human immunodeficiency virus (HIV) in vitro. The structure contains allophenylnorstatine [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] with a hydroxymethylcarbonyl isostere. We asked whether this experimental anti-HIV agent could exert its activity in vitro in the presence of relatively high concentrations of fetal calf serum (FCS) and assessed its protein-binding properties by using fresh human plasma preparations. The 50 and 75% inhibitory concentrations of KNI-272 against HIV type 1 replication in vitro were 3- to 5-fold and 5-fold higher in the presence of 50% FCS and 15- to 25-fold and 25- to 100-fold higher in the presence of 80% ECS, respectively, than those with 15% FCS, whereas the antiviral activity of 2',3'-dideoxyinosine was not significantly affected by FCS concentrations in the culture. Detailed studies of the protein binding of KNI-272 suggest that in human plasma binding occurs predominantly to alpha 1-acid glycoprotein and that KNI-272 is probably extensively (approximately 98 to 99%) protein bound at concentrations likely to be achieved in the circulation. Thus, higher levels of KNI-272 in plasma may be required when this compound undergoes clinical trials relative to those inferred from in vitro data involving the use of 10 to 15% FCS-containing culture media. The current data may have a relevance to other antiretroviral drugs that are under development and that have a high protein-binding capacity.
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PMID:Protein binding of human immunodeficiency virus protease inhibitor KNI-272 and alteration of its in vitro antiretroviral activity in the presence of high concentrations of proteins. 806 46

Human immunodeficiency virus (HIV), the retrovirus believed to be the cause of acquired immunodeficiency syndrome (AIDS), infects a variety of CD4+ cells, including lymphocytes and cells of the monocyte/macrophage lineage. Encoded in the HIV genome are several precursor proteins that must undergo proteolytic cleavage to yield functional proteins. The gag precursor protein of HIV (p55) is cleaved by a virally encoded aspartate protease (HIV protease). Because cleavage of p55 is required for viral maturation and infectivity, inhibition of HIV protease is an attractive target for therapy designed to block the progression of HIV infection. Inhibitors of HIV protease from a variety of chemical classes have been synthesized and antiviral activity has been demonstrated in lymphocytes and cells from the monocyte/macrophage lineage. A few HIV protease inhibitors have progressed to the clinic and some have shown promise in early trials. There are, however, several important issues that will affect the development of a successful HIV protease inhibitor, including cell and tissue distribution and immunotoxicity. These issues are tissue distribution and immunotoxicity. These issues are discussed, with an emphasis on the complexities posed by cells of the monocyte/macrophage lineage.
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PMID:HIV protease inhibitors: effects on viral maturation and physiologic function in macrophages. 808 11

Inhibitors of the human immunodeficiency virus type 1 (HIV-1) protease represent a promising addition to the available agents used to inhibit virus replication in a therapeutic setting. HIV-1 is capable of generating phenotypic variants in the face of a variety of selective pressures. The potential to generate variants with reduced sensitivity to a protease inhibitor was examined by selecting for virus growth in cell culture in the presence of the protease inhibitor A-77003. Virus variants grew out in the presence of the inhibitor, and these variants encoded proteases with reduced sensitivity to the inhibitor. Variants were identified that encoded changes in each of the three subsites of the protease that interact with the inhibitor. HIV-1 displays significant potential for altering its interaction with this protease inhibitor, suggesting the need for multiple protease inhibitors with varying specificities.
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PMID:Selection of multiple human immunodeficiency virus type 1 variants that encode viral proteases with decreased sensitivity to an inhibitor of the viral protease. 820 33

A synthetic peptide, RPI 312, that specifically inhibits the protease of the human immunodeficiency virus type 1 (HIV-1) showed a potent inhibition on virus production, maturation, and infectivity. Treatment with this agent prevented the cleavage of Gag protein at the site between p17 and p24 in HIV-1 chronically infected MOLT-4 cells as well as in the released virus. Passage of HIV-1 in the presence of gradually increasing concentrations of this protease inhibitor resulted in emergence of a variant that could evade the drug effects. In the resistant variant the maturation of Gag proteins appeared normal, but its infectivity was reduced compared with that of the parent virus. The nucleotides coding the amino acids at and around the cleavage site between Gag proteins p17 and p24 were not changed. One point mutation (A-->G) at site 2082 of the pol gene that resulted in one amino acid change at site 84 of the protease from isoleucine to valine (I-84-->V) could be detected in the resistant variant. An HIV-1 infectious DNA clone with the I-84-->V mutation also showed reduced sensitivity to this protease inhibitor. The findings that the resistant variant had lower infectivity and was still affected by higher doses of the drug support the speculation that resistance to protease inhibitors may not be as problematic as other drug resistance.
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PMID:Generation and characterization of a human immunodeficiency virus type 1 (HIV-1) mutant resistant to an HIV-1 protease inhibitor. 825 33

Protease inhibitors are another class of compounds for treatment of human immunodeficiency virus (HIV)-caused disease. The emergence of resistance to the current anti-HIV drugs makes the determination of potential resistance to protease inhibitors imperative. Here we describe the isolation of an HIV type 1 (HIV-1) resistant to an HIV-protease inhibitor. Serial passage of HIV-1 (strain RF) in the presence of the inhibitor, [2-pyridylacetylisoleucylphenylalanyl-psi (CHOH)]2 (P9941), failed to yield a stock of virus with a resistance phenotype. However, variants of the virus with 6- to 8-fold reduced sensitivity to P9941 were selected by using a combination of plaque assay and endpoint titration. Genetic analysis and computer modeling of the variant proteases revealed a single change in the codon for amino acid 82 (Val-->Ala), which resulted in a protease with lower affinity and reduced sensitivity to this inhibitor and certain, but not all, related inhibitors.
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PMID:In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV type 1 protease. 835 53


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