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)

HIV-infected individuals, who received 3TC monotherapy over one year, generally had lower plasma viral burden than at base-line. This was in spite of high-level resistance to this compound and the appearance of the M184V substitution in the HIV reverse transcriptase (RT) gene, responsible for diminished sensitivity to 3TC. This apparent contradiction is explained by an increase in the fidelity of the HIV RT, conferred by the M184V mutation, on the basis of the following observations. First, titers of viral neutralizing antibodies, as measured against sequential autologous HIV isolates, remained stable in this population in contrast to rapid declines in patients treated with other drugs. This suggests that increased fidelity of M184V RT may limit variability in the HIV env gene and result in protracted effectiveness of anti-viral immune responsiveness. Second, recombinant HIV, that contained the M184V substitution in RT, could not replicate in the presence of d4T, AZT, Nevirapine, Delavirdine or Saquinavir, using previously described protocols for the generation of drug resistance in vitro.
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PMID:Increased fidelity of drug-selected M184V mutated HIV-1 reverse transcriptase as the basis for the effectiveness of 3TC in HIV clinical trials. 920 7

Several anti-HIV drugs acting on different steps of virus replication were tested in our experimental model of primary monocyte/macrophages; the results were compared with the activity found in lymphocytes. Nucleoside analogues (AZT, ddI, ddC, d4T, PMEA, 3TC etc.) show greater activity in macrophages (M/M) than in lymphocytes. In particular, the EC50 of AZT, ddC, and ddI in M/M is 2- to 100-fold lower than that found in lymphocytes. This greater efficacy of nucleoside analogues in M/M depends on the enhancement of their chain-terminating activity by the low levels of endogenous deoxynucleoside-triphosphates (dNTP) usually found in resting cells such as M/M. Non-nucleoside reverse transcriptase inhibitors (NNRTI) do not act as chain terminators (thus their antiviral effect is not related to the intracellular concentrations of dNTP); as a consequence the activity of TSAO, HEPT, TIBO, and other NNRTI tested in M/M is similar to that found in lymphocytes. Regarding inhibitors of binding and fusion of HIV, we found that their anti-HIV activity is markedly decreased (or even nullified) when M/M are treated with cytokine activators of M/M function and enhancers of HIV replication. More relevant from a clinical standpoint, protease inhibitors are able to inhibit HIV replication in chronically infected macrophages (i.e., cells carrying the proviral genome already integrated in the host genome). All other inhibitors of late stage of virus life cycle tested (antisense-rev, anti-tat, interferon-alpha and -gamma, phosphorothioate analogues, GLQ-223, etc.) were totally inactive in chronically infected macrophages. The different effects of various classes of HIV inhibitors in lymphocytes and macrophages suggests that AIDS therapy should consider all aspects of the pathogenesis of HIV infection and must be restricted to drugs, or combinations of drugs, active against both lymphocytes and M/M in all body compartments where the virus hides and replicates.
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PMID:Inhibition of replication of HIV in primary monocyte/macrophages by different antiviral drugs and comparative efficacy in lymphocytes. 922 5

2',3'-Dideoxyadenosine (ddA), 2',3'-didehydro-2',3'-dideoxyadenosine (d4A) and their lipophilic 5'-monophosphate triester (aryloxyphosphoramidate) prodrugs were evaluated for their anti-retrovirus and anti-hepatitis B virus activity in various cell culture models. The aryloxyphosphoramidate derivatives of ddA (Cf 1093) and d4A (Cf 1001) showed markedly superior (100-1000-fold) efficacies than the parent drugs against human immunodeficiency virus type 1 (HIV-1), HIV-2, simian immunodeficiency virus (SIV), Moloney murine sarcoma virus (MSV) and human hepatitis B virus (HBV) replication regardless of the cell type in which the virus replication was studied (i.e., human T-lymphocyte CEM, MT-4, Molt/4 and C8166 cells, peripheral blood lymphocytes (PBL), monocyte/macrophages (M/M), murine embryo fibroblasts and human hepatocyte cells). Also the selectivity index (ratio of cytotoxic concentration/antivirally effective concentration) of both aryloxyphosphoramidate prodrugs was markedly increased. In particular the d4A prodrug Cf 1001 showed a selectivity index of 300-3000 as compared with 2-3 for the parental d4A in established laboratory cell lines. Also Cf 1001 had a selectivity index of 400-650 in HIV-1-infected PBL and M/M, respectively. Both Cf 1001 and Cf 1093 were equally efficient as 3TC (lamivudine) in inhibiting HBV replication in hepatocytes, and rank among the most potent HIV and HBV inhibitors reported so far in cell culture.
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PMID:Conversion of 2',3'-dideoxyadenosine (ddA) and 2',3'-didehydro-2',3'-dideoxyadenosine (d4A) to their corresponding aryloxyphosphoramidate derivatives markedly potentiates their activity against human immunodeficiency virus and hepatitis B virus. 923 55

Two mutants of HIV-1 reverse transcriptase (RT) associated with high-level resistance of the virus to AZT (RT-AZT: D67N, K70R, T215Y, K219Q, and M41L) or 3-TC (RT-3TC: M184V) were expressed in Escherichia coli and purified. None of these mutants showed significant changes in the affinity and kinetics of binding to a DNA/DNA primer/template. RT-AZT was investigated in detail with respect to its kinetics of incorporation of nucleotides. No change in the relative rates of TMP and AZTMP incorporation could be detected for RT-AZT with respect to wild type RT. These results imply that there is no increased discrimination against AZTTP in the mutant. This was found for DNA/DNA and DNA/RNA primer/template. Additionally, rapid kinetics of incorporation of 3'-amino-3'-deoxythymidine 5'-monophosphate (a possible metabolite of AZT) were investigated and compared with TMP incorporation, but no difference in its relative rates of incorporation between wild type RT and RT-AZT was detected. In contrast, the already very slow rate of incorporation of 3-TCMP seen with wild type enzyme was drastically reduced (by a factor of 23 and 36 with DNA/DNA primer/template and DNA/RNA primer/template, respectively) for RT-3TC, showing a clear correlation between in vitro and in vivo effects. The affinity of 3-TCTP to the RT-3TC-primer/template complex was not affected by the mutation M184V. A 1.6-fold cross-resistance to ddATP, the converted form of the prodrug ddI, could also be shown for RT-3TC, but no cross-resistance to ddCTP was detected. Additionally, rapid kinetics of AZTMP incorporation by RT-3TC were investigated. There was an indication of a slightly higher rate of incorporation of AZTMP by RT-3TC than wild type RT.
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PMID:Single-step kinetics of HIV-1 reverse transcriptase mutants responsible for virus resistance to nucleoside inhibitors zidovudine and 3-TC. 925 28

Nelfinavir mesylate (formerly AG1343) is a potent and selective, nonpeptidic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease that was discovered by protein structure-based design methodologies. We evaluated the antiviral and cytotoxic effects of two-drug combinations of nelfinavir with the clinically approved antiretroviral therapeutics zidovudine (ZDV), lamivudine (3TC), dideoxycytidine (ddC; zalcitabine), stavudine (d4T), didanosine (ddI), indinavir, saquinavir, and ritonavir and a three-drug combination of nelfinavir with ZDV and 3TC against an acute HIV-1 strain RF infection of CEM-SS cells in vitro. Quantitative assessment of drug interaction was evaluated by a universal response surface approach (W. R. Greco, G. Bravo, and J. C. Parsons, Pharm. Rev. 47:331-385, 1995) and by the method of M. N. Prichard and C. Shipman (Antiviral Res. 14:181-206, 1990). Both analytical methods yielded similar results and showed that the two-drug combinations of nelfinavir with the reverse transcriptase inhibitors ZDV, 3TC, ddI, d4T, and ddC and the three-drug combination with ZDV and 3TC resulted in additive to statistically significant synergistic interactions. In a similar manner, the combination of nelfinavir with the three protease inhibitors resulted in additive (ritonavir and saquinavir) to slightly antagonistic (indinavir) interactions. In all combinations, minimal cellular cytotoxicity was observed with any drug alone and in combination. These results suggest that administration of combinations of the appropriate doses of nelfinavir with other currently approved antiretroviral therapeutic agents in vivo may result in enhanced antiviral activity with no associated increase in cellular cytotoxicity.
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PMID:Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro. 933 41

Potent antiretroviral therapy can reduce plasma HIV RNA levels below the threshold of detection for periods of a year or more. The magnitude of HIV RNA reduction in the lymphoid tissue in patients with suppression of HIV RNA levels in plasma beyond 6 months has not been determined. We evaluated levels of HIV RNA and DNA and characterized resistance mutations in blood and inguinal lymph node biopsies obtained from 10 HIV-infected subjects who received 36-52 weeks of indinavir (IDV)/zidovudine (ZDV)/lamivudine (3TC), IDV, or ZDV/3TC. After 1 year of therapy, viral RNA levels in LN of individuals remained detectable but were log10 = 4 lower than in subjects on the triple drug regimen with interruption of therapy or in those treated with ZDV/3TC alone, who had viral loads in their lymph nodes indistinguishable from those expected for untreated patients. In all cases viral DNA remained detectable in lymph nodes and peripheral blood mononuclear cells (PBMC). When plasma virus suppression was incomplete, lymph node and PBMC cultures were positive and drug resistance developed. These studies indicate that pronounced and sustained suppression of plasma viremia by a potent antiretroviral combination is associated with low HIV RNA levels in the lymph nodes 1 year after treatment. Conversely, the persistence of even modest levels of plasma virus after 1 year of treatment reflects ongoing viral replication, the emergence of drug resistance, and the maintenance of high burdens of virus in the lymph nodes.
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PMID:Reduction of HIV-1 in blood and lymph nodes following potent antiretroviral therapy and the virologic correlates of treatment failure. 935 91

The nucleoside drug lamivudine (3TC) triggers the selection of resistant forms of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) with a substitution of amino acid 184Met. The 3TC-resistant RT enzymes 184Val and 184Ile exhibit a processivity defect in in vitro assays that correlates with reduced replication of the corresponding virus variants in primary cells. However, no replication defect is apparent for these two mutants in the transformed T-cell line SupT1. One obvious difference between the two cell types is the intracellular deoxynucleoside triphosphate (dNTP) level. Primary cells have a much smaller dNTP pool, and this cellular condition may emphasize the processivity defect of the codon 184 RT variants. Alternatively, cell-specific cofactors that influence the process of reverse transcription may exist. Such accessory factors may be packaged into the virion to exert an effect on the RT enzyme. To discriminate between these possibilities we performed additional assays with the wild-type and mutant RT enzymes. The RT proteins were either isolated from virions produced by primary and transformed cell types or expressed as recombinant protein. We also performed infection assays with cells treated with a drug that reduces the intracellular dNTP pool. Furthermore, reverse transcription was studied within virus particles in the endogenous assay, which allows for the manipulation of the dNTP level. The combined results indicate that the enzymatic defect of the 3TC-resistant HIV-1 variants is stressed at low dNTP concentrations.
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PMID:Limiting deoxynucleoside triphosphate concentrations emphasize the processivity defect of lamivudine-resistant variants of human immunodeficiency virus type 1 reverse transcriptase. 937 54

Sho-saiko-to (SST), a traditional Kampo medicine, has been examined for its inhibitory effect on human immunodeficiency virus type 1 (HIV-1) replication in peripheral blood mononuclear cells (PBMCs). SST alone moderately inhibited HIV-1 replication at a concentration of 25 microg/ml. When SST was combined with zidovudine (AZT), lamivudine (3TC) or AZT plus 3TC, SST enhanced the anti-HIV-1 activity of 3TC. In contrast, SST slightly enhanced the anti-HIV-1 activity of AZT plus 3TC but did not enhance the activity of AZT alone. These results suggest that the combination of SST and 3TC has potential as a chemotherapeutic modality of HIV-1 infection.
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PMID:Sho-saiko-to, a traditional Kampo medicine, enhances the anti-HIV-1 activity of lamivudine (3TC) in vitro. 940 12

Adefovir (PMEA, 9-(2-phosphonomethoxyethyl)adenine), an acyclic nucleoside phosphonate analogue is active against retroviruses, hepadnaviruses and herpesviruses. Adefovir dipivoxil, an orally bioavailable prodrug of adefovir is currently in phase III clinical trials for the treatment of HIV and phase II clinical trials for the treatment of HBV infections. PMPA (9-(2-phosphonomethoxypropyl)adenine) is a related acyclic nucleoside phosphonate analogue that has demonstrated potent anti-SIV activity in rhesus macaques and recently has shown marked anti-HIV activity in a phase I clinical study. Since the standard of care for AIDS patients has become combination therapy, the effects of other antiretroviral compounds (d4T, ddC, AZT, ddI, 3TC, nelfinavir, ritonavir, indinavir, and saquinavir) on the anti-HIV activity of adefovir and PMPA were investigated in vitro. Adefovir and PMPA both demonstrated strong synergistic anti-HIV activity in combination with AZT. Adefovir demonstrated minor to moderate synergistic inhibition of HIV replication in combination with PMPA, d4T, ddC, nelfinavir, ritonavir, and saquinavir. PMPA demonstrated minor synergistic inhibition of HIV replication in combination with ddI and nelfinavir (and adefovir). All other combinations showed additive inhibition of HIV replication in vitro. Importantly, no antagonistic interactions were measured for any of the adefovir or PMPA combinations.
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PMID:Anti-HIV activity of adefovir (PMEA) and PMPA in combination with antiretroviral compounds: in vitro analyses. 944 65

The development of HIV protease inhibitors has dramatically improved the treatment prognosis of HIV-infected patients. The treatment, however, is associated with the potential for adverse events that are unique to protease inhibitors. One of them, Indinavir, can lead to the development of urinary stones. Three weeks after starting treatment with Indinavir, Zidovudine and Lamivudine, a 66-year-old patient developed symptomatic hydronephrosis on the right side due to multiple Indinavir stones blocking the ureter. Microhematuria and characteristic crystals were found in the urine. After interruption of treatment and increased fluid intake, the crystallurea was not longer detectable and the patient became asymptomatic within 3 days. Nephrostomy and ureteral stent placement were not necessary. Patients on treatment with Indinavir are required to maintain a fluid intake of at least 1.5-2 l/day to reduce the risk of crystallization and urinary stones. Pharmacologic metaphylaxis to prevent crystallization is not recommended.
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PMID:Indinavir urinary stones as origin of upper urinary tract obstruction. 944 46


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