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PubMed2001

Site-directed mutagenesis of human immunodeficiency virus type 1 reverse transcriptase at amino acid position 138.

TSAO derivatives represent a class of nonnucleoside reverse transcriptase inhibitors (NNRTIs) that consistently select for the Glu138Lys resistance mutation in HIV-1 reverse transcriptase (RT). Seven RT mutants (i.e., Ala, Asp, Gln, Gly, Lys, Phe, and Tyr) were constructed by site-directed mutagenesis. The mutant Glu138Asp, Glu138Lys, Glu138Gln, Glu138Ala, and Glu138Gly RTs retained marked catalytic activity. In contrast, the Glu138Phe and Glu138Tyr RT mutants showed poor RNA-dependent DNA polymerase activity (30 and 4% of wild-type, respectively). TSAO derivatives lost their inhibitory activity against all mutant enzymes, except against the closely related Glu138Asp RT mutant that remained as sensitive to TSAOs as did wild-type RT. Other NNRTIs, including delavirdine, emivirine, and UC-781, and the NRTI ddGTP retained pronounced inhibitory activity against all mutant enzymes. When the amino acid mutations at position 138 of RT were introduced in recombinant virus clones, the sensitivity/resistance spectrum obtained toward the TSAOs and other NNRTIs was similar to those observed for the isolated recombinant mutant enzymes. The Glu138Lys RT mutant virus had the most marked resistance to TSAOs, followed by the Glu138Gln, Glu138Phe, Glu138Gly, Glu138Tyr, and Glu138Ala virus mutants. The Glu138Asp RT mutant virus kept full sensitivity to the TSAO derivatives. Mixtures of Glu138Lys RT mutant virus with the other virus clones mutated at the 138 position resulted in all cases, except for the Glu138Asp and Glu138Gly RT mutant viruses, in an outgrowth of the Glu138Lys RT mutant virus. Since the Glu138Lys RT proved most resistant to TSAO derivatives, was among the most catalytically efficient enzymes, and resulted in highly replication-competent virus, our data explain why the Glu138Lys RT mutant virus strains but not virus strains containing other amino acids at position 138 invariably emerge in cell cultures under TSAO drug pressure.

Alanine↗

PubMed2003

Nevirapine-selected mutations Y181I/C of HIV-1 reverse transcriptase confer cross-resistance to stavudine.

Stavudine administration did not increase the frequency of Y181I/C reverse transcriptase (RT) mutations in non-nucleoside reverse transcriptase inhibitor (NNRTI)-treated patients. However, recombinant Y181C HIV-1 showed reduced stavudine susceptibility with respect to both recombinant wild-type and K103N HIV-1 strains. In addition, recombinant Y181I RT enzyme showed reduced susceptibility to stavudine with respect to both wild-type and K103N RT. A previously unnoticed role of Y181I/C RT changes selected by nevirapine or other NNRTI in determining stavudine resistance is documented.

Antiretroviral Therapy, Highly Active↗

PubMed1980

Effects of polyethylene glycol on reverse transcriptase and other polymerase activities.

Polyethylene glycol enhances reverse transcription, augmenting both the rate and duration of polymerization. The effective mean molecular weight of polyethylene glycol is 6000 and the optimal concentration is 12% (w/w). Polyethylene glycol is effective on the reverse transcriptase reaction of all ten type B, C, and D viruses tested under a variety of exogenous, endogenous, and reconstitution assay systems, including the highly efficient conditions involving calf thymus DNA oligonucleotide primers. By three methods of synthesis, polyethylene glycol increased the yields of complementary [3H]DNA by a factor of 1.8--6.5. Polyethylene glycol does not alter the divalent cation requirements of the specificities of the enzyme. Complementary [3H]DNAs made in the presence of polyethylene glycol are indistinguishable in terms of size and sequence complementarity from those made in the absence of the polymer. The stimulatory effect was partly due to the ability of polyethylene glycol to stabilize reverse transcriptase. Preliminary tests indicate that polyethylene glycol also stimulates other nucleotide polymerases, such as the DNA-dependent DNA and RNA polymerases of Escherichia coli and the terminal transferase of calf thymus.

Escherichia coli↗

PubMed1979

Adsorption, penetration, and uncoating of murine leukemia virus studied by using its reverse transcriptase.

A procedure using the virus-associated reverse transcriptase was developed for following the kinetics of adsorption, penetration, and uncoating of murine leukemia virus. Viral adsorption to cell membrane was determined by assaying this enzyme activity in isolated debris of mechanically disrupted cells after infection with murine leukemia virus in the presence of actinomycin D. At 37 degrees C, viral adsorption proceeded at a high initial rate, but after 5 min of incubation with the virus, it gradually slowed down. At 4 degrees C, viral adsorption was slower but proceeded at a linear rate. Intracellular virus was determined by centrifuging the cytoplasmic fraction of the disrupted cells at 105,000 x g for 45 min and assaying reverse-transcriptase activity in the high-speed pellet thus obtained. Sucrose gradient analysis of the enzyme activity recovered from the cytoplasm of infected cells indicated that this activity represented intact virus particles. No appreciable amount of such particles was recovered from the cytoplasm of cells infected at 4 degrees C. This indicates that the virions recovered from the cytoplasm of cells infected at 37 degrees C are indeed intracellular virus particles which penetrated into the cells and not just membrane-bound particles mechanically released to the cytoplasmic fraction during cell disruption. By this procedure intracellular virus was found to accumulate in the cytoplasm, reaching a maximal level within 20 min. The accumulated intracellular virus particles gradually disappeared from the cytoplasm, evidently due to their uncoating which was completed within 80 min.

Adsorption↗

PubMed1978

Sodium pyrophosphate inhibition of RNA.DNA hybrid degradation by reverse transcriptase.

Sodium pyrophosphate inhibits synthesis of anticomplementary DNA during a reverse transcriptase (RNA-directed DNA nucleotidyltransferase, EC 2.7.7.7) catalyzed reaction. In the presence of pyrophosphate, the complementary DNA remains stably complexed to the RNA template. In the absence of pyrophosphate, the DNA. RNA hybrid template is degraded and anticomplementary DNA is synthesized. High concentrations of additives containing phosphodiester bonds appear to inhibit the ribonuclease H activity (hybrid nuclease, EC 3.1.4.34) of the reverse transcriptase, therby preventing formation of RNA primers necessary for the synthesis of anticomplementary DNA.

Diphosphates↗

PubMed1991

Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture.

We have recently described a nonnucleoside compound that specifically inhibits the reverse transcriptase of human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS. This compound, nevirapine (BI-RG-587), interacts with highly conserved tyrosine residues at positions 181 and 188 in the reverse transcriptase to inhibit the recombinant enzyme and virus replication in cell culture with 50% inhibitory concentrations in the 40 nM range. HIV-1 variants resistant to nevirapine emerged with passage in cell culture in the presence of drug. This resistant phenotype was stable with continued passage in the absence of drug. These mutants had a substitution of cysteine for the tyrosine at position 181. Introduction of this mutation into the recombinant enzyme increased the inhibitory concentration of nevirapine 100-fold. Substitution of cysteine for tyrosine at residue 181 into the wild-type viral genome conferred a similar reduction in susceptibility to nevirapine. Mutants were also resistant to a tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione derivative and two 6-phenylthiouracil derivatives but retained their sensitivity to the other reverse transcriptase inhibitors, 3'-azido-3'-deoxythymidine and foscarnet.

Amino Acid Sequence↗

PubMed2003

Mutation patterns of the reverse transcriptase genes in HIV-1 infected patients receiving combinations of nucleoside and non nucleoside inhibitors.

A genotyping assay was used to define human immunodeficiency virus type 1 (HIV-1) reverse transcriptase codons in plasma samples from 80 HIV-1 patients extensively treated with two nucleoside reverse transcriptase (zidovudine and lamivudine) and one non nucleoside reverse transcriptase (nevirapine) inhibitor. The frequencies of T215S/Y/F, M41L, D67N, L210W K70R, K219Q mutations, detectable in plasma samples, conferring resistance to zidovudine were 61.2, 56.2, 36.2, 31.5, 27.5 and 17.5%, respectively. Mutations (M184V or M184I) conferring resistance to lamivudine were detected in an extremely high percentage of patients (61%). Among mutations correlated to high (K103N, V106A, Y181C/I, Y188C/H/L, G190A/C/E/Q/S/T) or moderate (V108I, V118I) levels of nevirapine resistance, the predominant amino acid change was a substitution at 103 codon, present in 24 of 80 samples tested. Finally Q151M, the marker mutation able to confer resistance to all nucleoside analogues, was detected in seven patients with a viral load of between 1 x 10(4) and 9 x 10(4) HIV-1 RNA copies/ml. The relationship between the genotype and the viral load showed that the incidence of some specific mutations [M41L, T215Y (correlated to zidovudine resistance) and K103N (correlated to all NNRTIs drugs)] significantly (P=0.001) increased with higher viral load. Our results, albeit limited to a small cohort, showed a high frequency of mutations correlated to drugs in use, suggesting a need for therapeutic change in the near future and demonstrating that the development of genotyping tests helps to guide the therapeutic management of HIV-1 infected people. Our data highlight the dangers of selecting antiretroviral therapy without previous antiretroviral drug testing. Although the cost of these assays is a concern, prescribing inefficacious drugs could create serious problems for HIV-1 patients.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Emergence and genetic evolution of HIV-1 variants with mutations conferring resistance to multiple reverse transcriptase and protease inhibitors.

The emergence of genotypic resistance in protease and reverse transcriptase (RT) gene regions was longitudinally evaluated in plasma samples from a group of 12 HIV-1-infected patients treated with different combination of antiretroviral therapies and selected on the basis of their clinical failure. Complex mutational patterns in the reverse transcriptase gene were observed. In particular, combinations of AZT (41L, 67N, 70R, 210W, and 219Q/E) and 3TC (184M) were seen in 10 patients. Two patients presented codon 151 multinucleoside analogue resistance (MNR). Additionally, seven patients harbored RT nonnucleoside analogue-related resistance substitutions (98G, 103N, and 181C). Multiple protease-selected mutations were found in each patient with an average of six substitutions per patient, with 10I/F/V, 63P, 71V, 82A/T, 84V, and 90M being the most prevalent substitutions. Overall, these results showed that for most patients virological failure was coupled with detectable genotypic resistance. Furthermore, most patients exhibited genotypic resistance to almost all available anti-HIV-1 drugs. The high viral loads found in most patients at the end of the study suggest that the replication of these multidrug resistant viruses are not severely compromised. Phylogenetic analysis of these pol sequences revealed that a specific HIV-1 genotype prone to develop multidrug resistance was not found.

Adult↗

PubMed2000

Immunogenic properties of reverse transcriptase of HIV type 1 assessed by DNA and protein immunization of rabbits.

Genetic immunization may be one way to prime individuals for a subsequent broad anti-HIV-1 immune response. Reverse transcriptase of HIV-1 (RT) presents a selective target for attempts to arrest replication of HIV-1. Rabbits immunized with a plasmid carrying the gene for reverse transcriptase HIV-1 (RT DNA) developed potent antibody and cellular responses to the gene product. The immunogenic properties of RT DNA and recombinant reverse transcriptase were compared in rabbits. The specific immune responses were similar to those reported previously for HIV-1 infected humans. The array of B and T cell epitopes recognized in RT DNA-immunized rabbits was broader than in rabbits immunized with the recombinant RT. We localized seven novel B and T cell epitopes and concordance between B cell and helper T cell epitopes was observed. B cell epitopes of RT induced proliferation of peripheral blood mononuclear cells and were active as helper T cell epitopes. T cell-proliferative responses to the epitopes of RT preceded or paralleled the production of antibodies of the same specificity. Subdomains of reverse transcriptase involved in the enzymatic activity of RT were highly immunogenic. Anti-RT IgG partially inhibited reverse transcription in vitro.

Amino Acid Sequence↗

PubMed1987

Comparison of antigen assay and reverse transcriptase assay for detecting human immunodeficiency virus in culture.

We compared an antigen capture assay (Abbott Laboratories, North Chicago, Ill.) with a reverse transcriptase assay to identify and quantify human immunodeficiency virus (HIV) in culture. In direct comparisons of serial dilutions of lymphadenopathy-associated virus type 1, the antigen assay was 100-fold more sensitive than the reverse transcriptase assay in detecting the virus. The antigen assay reacted strongly with 60 different HIV isolates but did not cross-react with human T-cell lymphotropic virus type I, human T-cell lymphotropic virus type II, cytomegalovirus, varicella-zoster virus, herpes simplex virus type 1, Epstein-Barr virus, adenovirus type 5, or poliovirus type 1 or with extracts from four different control human cell lines and eight different phytohemagglutinin-stimulated normal human lymphocytes. Peripheral blood lymphocyte samples from 50 individuals were evaluated by both the antigen assay and the reverse transcriptase assay. The cells from the 34 seropositive individuals were all positive by the antigen assay (range, 3 to 9 days; average time, 5.9 days) and the reverse transcriptase assay (range, 7 to 16 days; average time, 9.6 days). Cells from the 16 seronegative individuals were negative by both assays. These results indicate that the antigen assay is an important addition to the monitoring of HIV production in the lymphocytes of infected patients.

Cell Line↗

PubMed2002

Sustained high proportion of zidovudine-resistant HIV variants despite prolonged substitution of zidovudine by other nucleoside reverse transcriptase inhibitors.

The consequences of zidovudine (ZDV) replacement by other nucleoside reverse transcriptase inhibitors on the expression of resistance mutations at codons 215 and 41 of the reverse transcriptase (RT) gene was investigated prospectively in 66 patients harboring mutant genotypes who were changed to an effective two- or three-drug combination antiretroviral regimen. Quantitation of mutant (MUT) viral populations at codon 215 by means of RT-PCR with differential hybridization of amplicons specific for MUT and wild (WT) variants revealed no difference in the proportion of 215 MUT variants prior to (93.5 +/- 2.4%) and 12 to 20 months after (96.9 +/- 1.9%) ZDV replacement, independently of a therapeutic change for stavudine. The fitness of the variants harboring the ZDV-resistant MUT 215 genotype following drug withdrawal was calculated to be 96 to 99% of that of the variants harboring the WT 215 genotype. The apparent stability of ZDV-resistant variants in the study population may have two main complementary explanations: persistent selective pressure secondary to partial cross-resistance due to the new regimens given after the therapeutic alteration and suppression of viral replication after the therapeutic alteration that could have hampered the replacement of less fit variants by fitter variants. These findings indicate that, at least within 15 months following discontinuation of ZDV, an effective antiretroviral therapy is insufficient to allow for ZDV-resistant strains to disappear, and thus to allow for the safe re-introduction of the drug.

Adaptation, Physiological↗

PubMed1988

Two proteins with reverse transcriptase activities associated with hepatitis B virus-like particles.

Recent studies suggest that hepatitis B virus (HBV), despite being a DNA virus, replicates via an RNA intermediate (R. H. Miller, P. L. Marion, and S. W. Robinson, Virology 139:64-72, 1984; J. Summers and W. S. Mason, Cell 29:403-415, 1982). The HBV life cycle is therefore a permuted version of the RNA retroviral life cycle. Sequence homology between retroviral reverse transcriptase and the putative HBV polymerase gene product suggests the presence of an HBV reverse transcriptase (H. Toh, H. Hajashida, and T. Miyata, Nature (London) 305:827-829, 1983). As yet, there has been no direct evidence that reverse transcriptase activity is present in the viral particle. We used activity gel analysis to detect the in situ catalytic activities of DNA polymerases after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Our studies demonstrated that HBV-like particles secreted by a differentiated human hepatoma cell line transfected with genomic HBV DNA contain two major polymerase activities which migrate as approximately 90- and approximately 70-kilodalton (kDa) proteins. This demonstrated, for the first time, that HBV-like particles contain a novel DNA polymerase-reverse transcriptase activity. Furthermore, we propose that the 70-kDa reverse transcriptase may be produced by proteolytic self-cleavage of the 90-kDa precursor protein.

Cell Line↗

PubMed2002

Tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of HIV infection.

BACKGROUND: Tenofovir disoproxil fumarate (DF) is the first nucleotide reverse transcriptase inhibitor approved for use in combination with other antiretroviral agents in the treatment of HIV-1 infection in the United States. Unlike the nucleoside reverse transcriptase inhibitors, which must undergo 3 intracellular phosphorylation steps for activation. nucleotide analogues such as tenofovir require only 2 such steps. This reduction in the phosphorylation requirement has the potential to produce more rapid and complete conversion of the drug to its pharmacologically active metabolite. OBJECTIVE: This article describes the pharmacologic properties and potential clinical usefulness of tenofovir DF. METHODS: Relevant information was identified through searches of MEDLINE (1996-April 2002), Iowa Drug Information Service (1996-April 2002), and International Pharmaceutical Abstracts (1970-April 2002), as well as from meeting abstracts of major HIV/AIDS conferences (1996-2002), using the search terms tenofovir tenofovir disoproxil fumarate, PMPA, bis(POC)PMPA, GS-4331-05, acyclic nucleoside phosphonate, and nucleotide reverse transcriptase inhibitor. Additional information was obtained from material submitted to the US Food and Drug Administration by the manufacturer of tenofovir DF in support of its New Drug Application. RESULTS: In vitro, tenofovir DF has exhibited anti-HIV activity in various HIV-infected cell lines and has produced a synergistic or additive effect against HIV when combined with other antiretroviral agents. In adult humans, tenofovir has a volume of distribution of 0.813 L/kg, is minimally bound to plasma protein (7.2%), has a plasma elimination half-life of 12.0 to 14.4 hours, and is mainly excreted unchanged in urine (70%-80%). Dose adjustment based on sex or body weight does not appear to be necessary, although dose reduction may be necessary in the elderly; there are currently no data on tenofovir DF in renal or hepatic insufficiency. The results of clinical trials suggest the efficacy of tenofovir DF in reducing plasma levels of HIV-1 RNA when used as an add-on to a stable antiretroviral regimen. The most commonly (>3%) reported adverse events in clinical trials have included nausea, diarrhea, asthenia, headache, vomiting, flatulence, abdominal pain, and anorexia. The most commonly (>2%) reported laboratory abnormalities (grade III or IV) included increases in creatine kinase, triglycerides, amylase, aspartate aminotransferase, and alanine aminotransferase, as well as hyperglycemia and glucosuria. Serious adverse events leading to discontinuation of tenofovir DF were infrequent (5%), occurring with an incidence similar to that with placebo (8%). The recommended dosage of tenofovir DF in adults is 300 mg/d PO; pharmacokinetic and efficacy studies in children are ongoing. CONCLUSION: Although additional studies are needed, tenofovir DF appears to be a promising agent for the treatment of HIV infection.

Adenine↗

PubMed1989

Comparison of inhibitory activities of various antiretroviral agents against particle-derived and recombinant human immunodeficiency virus type 1 reverse transcriptases.

Several known antiretroviral agents were tested for their ability to inhibit the activities of human immunodeficiency virus type 1 reverse transcriptase purified from virions or from a recombinant Escherichia coli strain. The recombinant reverse transcriptase, a polypeptide of 66 kilodaltons, showed inhibition profiles indistinguishable from those of the virion-derived enzyme with all tested compounds, except for suramin and two dextran sulfates. These were more inhibitory to the recombinant enzyme, presumably because the E. coli-derived enzyme was more highly purified. The relative ease with which large quantities of recombinant enzyme can be prepared should facilitate the large-scale screening and identification of new potential inhibitors of the human immunodeficiency virus type 1 reverse transcriptase.

Antiviral Agents↗

PubMed1993

Early detection of de novo hepatitis C infection in patients after liver transplantation by reverse transcriptase polymerase chain reaction.

BACKGROUND: Reverse transcriptase polymerase chain reaction (RT-PCR) can detect the viral genome and show hepatitis C recurrence in patients who undergo transplantation for chronic hepatitis C viral (HCV) infection. We investigated the utility of an RT-PCR-based HCV assay for early detection of viral RNA in de novo HCV infection after liver transplantation. METHODS: Pretransplantation antibodies and explanation HCV viral RNA status were obtained from 117 patients. Follow-up liver biopsy specimens were examined for evidence of hepatitis activity. Plasma samples during the period of time of the biopsy were assayed for HCV antibody and viral RNA. RNA was extracted from samples and reverse transcribed to cDNA. cDNA was amplified by PCR, and products were detected by liquid hybridization. RESULTS: Clinical hepatitis developed in seventeen of 117 patients who, before transplantation, were HCV antibody negative and explant viral RNA negative. Ten patients were plasma PCR negative and had known non-hepatitis C causes for the biopsy findings. Of the remaining seven patients, five (70%) were plasma RT-PCR positive before seroconversion in matched plasma samples. CONCLUSIONS: In liver transplant patients, the incidence of de novo clinical hepatitis is low, and HCV viral RNA in de novo clinical hepatitis C infection can be detected in the absence of HCV antibodies.

Base Sequence↗

PubMed2002

Combinations against combinations: associations of anti-HIV 1 reverse transcriptase drugs challenged by constellations of drug resistance mutations.

The reverse transcriptase inhibitors still represent the majority of the clinically used anti-HIV drugs and constitute the main backbone of currently employed combinatorial regimens. A major obstacle to successfull chemotherapic eradication of HIV is the emergence of viral strains resistant to the drugs in use. Counteracting the emergence of resistance necessitates alternating the panel of agents employed. In order to rationally design alternative drug combinations, physicians not only must know the genotype of the emerging viral strains, but should also be able to correlate it with its resistant phenotype. However, resistant viral strains usually carry multiple mutations, whose reciprocal influences on the overall level of resistance are largely unknown. Moreover, the choice of agents to be combined must take in account drug-drug interactions and adverse metabolic effects. This review will outline the main pharmacological and clinical features of the currently utilised anti-reverse transcriptase drugs, as well as the correspondent resistance profiles selected during therapy. A major focus will be on the reciprocal influence of drug associations on their own metabolism as well as on the interacting effects of the selected combinations of drug resistance mutations.

Animals↗

PubMed1997

The newly synthetized pyridobenzoxazocynone inhibits HIV-1 reverse transcriptase activity.

We synthetized pyridobenzoxazocynone that differs in the enlarged eight-membered heterocyclic system from the basic structure of pyridobenzoxazepinones a known class of non-nucleoside HIV-1 reverse transcriptase inhibitors. Pyridobenzoxazocynone hydrochloride was found to inhibit HIV-1 reverse transcriptase activity. At concentration 0.35 microM the enzyme activity decreased by 64 +/- 14%. Higher concentrations of pyridobenzoxazocynone hydrochloride completely abolished the enzyme activity expressed as radioactivity of acid insoluble products. These results suggest that pyridobenzoxazocynones may represent a new class of HIV-1 reverse transcriptase inhibitors.

Gene Products, pol↗

PubMed1993

HIV-1-specific RT inhibitors: highly selective inhibitors of human immunodeficiency virus type 1 that are specifically targeted at the viral reverse transcriptase.

The TIBO, HEPT, nevirapine, pyridinone, BHAP, TSAO, and alpha-APA derivatives, although belonging to structurally diverging classes of molecules, share remarkable common features. They are specifically active against the reverse transcriptase of HIV-1 (TIBO and HEPT also, to a certain extent, against the reverse transcriptase of SIVagm strains), but not against the reverse transcriptases of HIV-2 or any other retroviruses. Nor are they active against any of the cellular DNA polymerases. These HIV-1-specific RT inhibitors seem to interact with a specific target site (YQYMDDLY) at positions 181-188, which is distinct from, but functionally and spatially related to, the substrate (dNTP) binding site. The tyrosine residues Y181 and Y188 play a crucial role in the interaction of TIBO and its congeners with their target site. The HIV-1-specific RT inhibitors have proven to inhibit the replication of various HIV-1 strains, including AZT-resistant HIV-1 strains, in different cell culture systems, including peripheral blood lymphocytes and monocyte/macrophages. In vitro they exhibit selectivity indexes of up to 5 orders of magnitude, which means that they are inhibitory to virus replication in cell culture at concentrations that are up to 100,000 times lower than the concentrations at which they are toxic to the host cells. As a rule, the HIV-1-specific RT inhibitors are orally bioavailable, as has been demonstrated with the TIBO and HEPT derivatives, nevirapine, pyridinones, and the alpha-APA derivatives in rats, dogs, monkeys, and humans. They sustain plasma drug levels that are well above the concentration required to inhibit virus replication in cell culture. Clinical studies have been undertaken with TIBO R82913, nevirapine, and pyridinones, and others (i.e., alpha-APA R89439) will soon follow. The problem of virus-drug resistance, which seems to readily emerge in vitro, will have to be addressed in the in vivo studies.

Drug Resistance, Microbial↗