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PubMed2004

Protease inhibitor and nonnucleoside reverse transcriptase inhibitor concentrations in the genital tract of HIV-1-infected women.

The pharmacokinetics of antiretrovirals (ARVs) in the female genital tract (FGT) are likely to influence vertical and sexual transmission of HIV, the development of viral resistance, and post-exposure prophylaxis regimens. This study is the first to compare ARV concentrations in direct aspirates of cervicovaginal fluid (CVF) and blood plasma (BP). This unique method provides direct assessment of concentrations without the confounding of cervicovaginal lavage dilution. Of 8 ARVs, CVF concentrations ranged from <10% to >100% of BP concentrations. These large differences in CVF penetration suggest that further research into ARV pharmacokinetics and drug efficacy in the FGT is necessary.

Adult↗
PubMed2002

Differences in cellular activation and apoptosis in HIV-infected patients receiving protease inhibitors or nonnucleoside reverse transcriptase inhibitors.

The mechanism of CD4(+) T cell depletion seen in HIV infection is largely mediated by increased apoptosis of these cells. The benefit of protease inhibitor (PI)-based antiretroviral therapy to CD4(+) T cell recovery seems to involve more than its antiviral activity, and a direct antiapoptotic effect of PIs has been proposed to explain it. To test this hypothesis we have analyzed directly, ex vivo, the effects of two different highly active antiretroviral therapy (HAART) regimens on the levels of activation and apoptosis of T lymphocytes. A total of 126 subjects (43 receiving PIs, 35 receiving NNRTIs, 27 untreated HIV carriers, and 21 uninfected control subjects) was included in the study. Apoptosis was measured in blood lymphocytes by flow cytometry, using annexin V labeling. A broad panel of monoclonal antibodies was used to characterize the different CD4(+) and CD8(+) lymphocyte subsets. Apoptosis was significantly increased in HIV-untreated subjects, whereas apoptosis levels did not differ when comparing HIV-positive subjects undergoing HAART and uninfected control subjects. Likewise, markers of activation were elevated in HIV-positive untreated patients, and declined in subjects receiving treatment. However, activated-memory CD8(+) T cells remained significantly higher in treated patients with respect to uninfected control subjects. No differences in the level of apoptosis or in immune activation markers were recognized when comparing subjects receiving PIs and those receiving NNRTIs. Antiretroviral therapy reduces apoptosis of CD4(+) and CD8(+) lymphocytes to normal levels without differences when comparing subjects receiving PI and NNRTI triple combinations. Despite complete suppression of viral replication, activated memory CD8(+) T cells remain significantly elevated in subjects receiving HAART, suggesting the persistence of residual HIV replication. If PIs provide a positive effect on CD4(+) counts beyond an antiviral effect, mechanisms other than apoptosis should be involved.

Anti-HIV Agents↗
PubMed2005

Superiority of protease inhibitors over nonnucleoside reverse-transcriptase inhibitors when highly active antiretroviral therapy is resumed after treatment interruption.

Forty-five human immunodeficiency virus (HIV)-infected patients stopped taking treatment but resumed taking it thereafter. All 11 who resumed treatment with their prior protease inhibitor (PI)-based regimen reattained an undetectable virus load, whereas this occurred for only 15 (44%) of 34 patients who resumed nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based treatment (P<.001). Distinct pharmacokinetics and resistance barriers may result in different performances for PIs and NNRTIs after treatment interruptions.

Antiretroviral Therapy, Highly Active↗
PubMed2002

Simultaneous separation of 11 protease and reverse transcriptase inhibitors for human immunodeficiency virus therapy by co-electroosmotic capillary zone electrophoresis.

In the present investigation, a co-electroosmotic capillary zone electrophoretic method is shown for the simultaneous separation of protease inhibitors and reverse transcriptase inhibitors, which are used as antiretroviral therapy drags against the human immunodeficiency virus (HIV). The investigated drugs carry basic amino groups, thus the electrophoretic system takes advantage of an acidic buffer electrolyte. In order to establish a strong cathodic electroosmotic flow (EOF), a poly-anionic surfactant is added to the background electrolyte. Thus, fast migration times due to a co-directional migration of analytes and EOF (co-electroosmotic CE) are obtained. The developed separation system exhibits good selectivities for the investigated compounds and sufficient sensitivity to monitor drug levels in the low ppm range in HIV positive patients who are treated by highly active anitiretroviral therapy.

Electrophoresis, Capillary↗
PubMed2000

[Non-nucleoside reverse transcriptase inhibitors].

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) directly inhibit the HIV-1 reverse transcriptase (RT) by binding in a reversible and non-competitive manner to the enzyme. The currently available NNRTIs are nevirapine, delavirdine, and efavirenz; other compounds are under evaluation. NNRTIs are extensively metabolized in the liver through cytochrome P450, leading to pharmacokinetic interactions with compounds utilizing the same metabolic pathway, particularly PIs, whose plasma levels are altered in the presence of NNRTIs. NNRTIs are drugs with a low genetic barrier, i.e. a single mutation in RT genoma induces a high-level of phenotypic resistance, preventing the use of NNRTIs as monotherapy. In naive patients, several trials have shown the value of NNRTIs in combination with nucleosides and/or protease inhibitors. Small pilot studies have shown that NNRTIs may be useful as second-line therapy. However, due to the rapid emergence of resistant virus to these compounds in case of incomplete viral suppression, NNRTIs should not be added to current failing antiretroviral regimen. The most common side-effect reported with nevirapine and delavirdine is rash. The incidence of rash is rather similar under these two compounds, but severe rash is less frequent with delavirdine. The most common adverse reactions reported with efavirenz are central nervous system complaints such as dizziness. Rash is reported less frequently than with nevirapine or delavirdine, and is usually mild. NNRTIs resistance mutations are located in the amino acid residues aligning the NNRTI-binding "pocket" site. High-level resistance is often associated with a single point mutation which develops within this site (especially codon groups 100 - 108 and 181 - 190). Patients failing on one NNRTI are very likely to possess multiple NNRTI resistance mutations. NNRTIs should always be used as part of a potent antiretroviral therapy to insure suppression of viral replication, thus circumventing the rapid selection of cross-resistant variants.

Anti-HIV Agents↗
PubMed2004

Clinical efficacy of antiretroviral combination therapy based on protease inhibitors or non-nucleoside analogue reverse transcriptase inhibitors: indirect comparison of controlled trials.

OBJECTIVE: To compare the clinical efficacy of triple antiretroviral regimens based on protease inhibitors and non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) in adults positive for antibodies to HIV-1. DESIGN: Systematic review and meta-analysis using indirect comparisons of clinical trials comparing three drug regimens based on two nucleoside reverse transcriptase inhibitors (NRTIs) and either a protease inhibitor or an NNRTI with two drug regimens (two NRTIs). Participants had no previous exposure to protease inhibitors or NNRTIs. DATA SOURCES: Medline, the Cochrane controlled trials register, Aidstrials, Aidsdrugs, conference proceedings, and trial registers. MAIN OUTCOME MEASURE: Progression to AIDS or death. RESULTS: 14 trials, totalling 6785 patients, were identified. Most patients had been exposed to an NRTI and had advanced immunodeficiency at baseline; 1096 progressed to AIDS or died. Seven trials assessed protease inhibitors based triple regimens and seven assessed NNRTI based triple regimens (nevirapine or delavirdine). Triple therapy was more effective than dual therapy. The effect was pronounced for protease inhibitor based regimens (odds ratio 0.49, 95% confidence interval 0.41 to 0.58) but non-significant for NNRTI based regimens (0.90, 0.71 to 1.15). Indirect comparison of the two regimens gave an odds ratio of 0.54 (0.49 to 0.73) in favour of protease inhibitor based treatments. Increases in CD4 cell counts were smaller and suppression of viral replication less with NNRTI based regimens. CONCLUSIONS: Indirect evidence shows that protease inhibitor based triple regimens are superior to regimens based on the NNRTIs nevirapine and delavirdine in patients with advanced immunodeficiency who have been exposed to NRTIs. Large trials with clinical end points are required.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Effects on immunological and virological outcome of patients using one protease inhibitor or one non-nucleoside reverse transcriptase inhibitor in a triple antiretroviral therapy: normal clinical practice versus clinical trial findings.

We compared the response of two standard 3-drug regimens containing two-nucleoside reverse transcriptase inhibitor (Zidovudine +Lamivudine) plus either a protease inhibitor (PIs) (Indinavir) or a non-nucleoside reverse transcriptase inhibitor (NNRTIs) (Efavirenz) among treatment-naïve or treatment-experienced HIV-infected persons. The obtained results will be compared to clinical trial findings. Through a retrospective study, we compared the virological and immunological response of 119 Tunisian HIV-1 infected patients (North Africa) who started for the first time/ in salvage use a triple antiretroviral treatment containing one NNRTI (group A1/group A2) or one PI (group B1/group B2). Viral load (VL) was analysed with Amplicor HIV-1 Monitor test and drug resistance mutations were examined by using two distinct line probe assays (LiPA). The analysis according to the received treatment showed an average of 0.45 log(10) drop in the mean VL among groups A2 and B2. For naïve patients, 62.5% of group A1 reached an undetectable VL versus 53.5% for group B1 (p < 0.001). With regard to the CD4 cell count change, we observed a mean increase of more than 65% versus baseline within group A1 in comparison with 42% for group B1 (p < 0.001). Genotypic resistance assays showed that patients of group A2 had significantly more resistance mutations than those of group B2 (2.66 vs. 0.75 (p = 0.0039)). Finally, 15 patients who were failing were switched to indinavir or efavirenz. When indinavir was replaced by efavirenz, we observed an increase in the plasma VL. With regard to the effects on immunological and virological outcome of patients using PIs or NNRTIs in a triple antiretroviral therapy, our observations in normal clinical practice supported the reported clinical trial findings but are not in favour of replacing indinavir by efavirenz in failing regimen.

Adult↗
PubMed2005

Simple and simultaneous determination of the hiv-protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir plus M8 nelfinavir metabolite and the nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine in human plasma by reversed-phase liquid chromatography.

Several studies suggest that therapeutic drug monitoring of protease inhibitors and nonnucleoside reverse transcriptase inhibitors may contribute to the clinical outcome of HIV-infected patients. Because of the growing number of antiretroviral drugs and of drug combinations than can be administered to these patients, an accurate high-performance liquid chromatographic (HPLC) method allowing the simultaneous determination of these drugs may be useful. To date, the authors present the first simultaneous HPLC determination of the new protease inhibitor atazanavir with all the others currently in use (M8 nelfinavir metabolite included) and the 2 widely used nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine. This simple HPLC method allows the analysis all these drugs at a single ultraviolet wavelength following a 1-step liquid-liquid extraction procedure. A 500-muL plasma sample was spiked with internal standard and subjected to liquid-liquid extraction using by diethyl ether at pH 10. HPLC was performed using a Symmetry Shield RP18 and gradient elution. All the drugs of interest and internal standard were detected with ultraviolet detection at 210 nm. Calibration curves were linear in the range 50-10,000 ng/mL. The observed concentrations of the quality controls at plasma concentrations ranging from 50 to 5000 ng/mL for these drugs showed that the overall accuracy varied from 92% to 104% and 92% to 106% for intraday and day-to-day analysis, respectively. No metabolites of the assayed compounds or other drugs commonly coadministered to HIV-positive patients were found to coelute with the drugs of interest or with the internal standard. This assay was developed for the purpose of therapeutic monitoring (TDM) in HIV-infected patients.

Alkynes↗
PubMed2004

High-performance liquid chromatography assay for the quantification of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors in human plasma.

An accurate, sensitive, and specific reverse-phase high-performance liquid chromatography (HPLC) assay for the simultaneous quantitative determination of HIV-protease inhibitors (PIs) (indinavir, IDV; amprenavir, APV; saquinavir, SQV; nelfinavir, NFV; ritonavir, RTV; and lopinavir, LPV) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) (nevirapine, NVP; delavirdine, DLV; and efavirenz, EFV) in human blood plasma is described. The method provides excellent resolution and peak shape for nine analytes through a linear gradient (36-86%) of 25% phosphate buffer (pH 4.5), 60% acetonitrile, 15% methanol, and 0.75 ml TFA, with a gradient mobile phase flow rate (0.9-1.1 ml) over 30 min run time. The optimized solid phase extraction (SPE) extraction method using (1.0 ml, 100mg BOND ELUT-C18 Varian) column provides a clean base line and high extraction efficiency using a 550 microl plasma sample. The method was validated over the range of 10-10,000 ng/ml for NVP, IDV, and SQV; 10-5000 ng/ml for EFV; 25-10000 ng/ml for APV; and 25-5000 ng/ml for DLV, NFV, RTV, and LPV. This method is accurate (average accuracies of three different concentrations ranged from 91 to 112%), and precise (within- and between-day precision measures ranged from 0.2 to 5.7% and 0.1 to 5.4%, respectively). This method is suitable for use in clinical pharmacokinetic studies as well as in therapeutic drug monitoring (TDM).

Chromatography, High Pressure Liquid↗
PubMed2001

Use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors among Medicaid beneficiaries with AIDS.

OBJECTIVES: This study compared the use of new antiretroviral treatments across sociodemographic subgroups during the 3 years after the introduction of these treatments and examined diffusion of the therapies over time. METHODS: Merged surveillance and claims data were used to examine use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (PI/NNRTIs) among New Jersey Medicaid beneficiaries with AIDS. RESULTS: In 1996, there were sharp disparities in use of PI/NNRTI therapy among racial minorities and injection drug users, even after control for other patient characteristics. These gaps had decreased by 1998. Higher PI/NNRTI treatment rates were also observed among beneficiaries enrolled in a statewide HIV/AIDS-specific home- and community-based Medicaid waiver program. CONCLUSIONS: Even within a population of individuals similar in regard to health coverage, there were substantial sociodemographic differences in use of PI/NNRTIs during the early years after their introduction. These differences narrowed as new treatments became standard. Participation in a case-managed Medicaid waiver program seems to be associated with a more appropriate pattern of use. These results suggest a need to address nonfinancial barriers to care.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Mutational analysis of Tyr-318 within the non-nucleoside reverse transcriptase inhibitor binding pocket of human immunodeficiency virus type I reverse transcriptase.

The highly conserved Tyr-318 is part of the non-nucleoside reverse transcriptase inhibitor (NNRTI)-specific lipophilic pocket of human immunodeficiency virus type I reverse transcriptase (RT) and makes contact within 4 A with the NNRTIs in all reported RT/NNRTI complexes. Using site-directed mutagenesis, six mutant RTs were constructed bearing the mutations Y318H, Y318K, Y318L, Y318C, Y318W, and Y318F. We found that only the Y318W and Y318F mutant RTs retained substantial RT activity, whereas the catalytic activities of the Y318K, Y318C, Y318H, and Y318L RT mutants were less than 5% of the wild-type activity. The Y318F mutant RT retained substantial sensitivity to the majority of NNRTIs tested, whereas the Y318W mutant RT showed varying degrees of resistance to NNRTIs. Subunit-specific site-directed mutagenesis revealed that there was no difference in the catalytic activity or resistance/sensitivity spectrum toward NNRTIs regardless of whether the Tyr-318 mutation was introduced in both subunits or only in the p66 subunit of RT. Recombinant viruses harboring the Y318F or Y318W mutation in the RT showed a similar resistance/sensitivity pattern to NNRTIs as their corresponding 318 mutant recombinant RTs. Our findings stress a functional or structural role for Tyr-318 in wild-type RT and argue for the design of novel NNRTIs that interact more closely with this amino acid in the NNRTI-specific pocket of human immunodeficiency virus type I RT.

Amino Acid Substitution↗
PubMed2002

High-performance liquid chromatographic method for the simultaneous determination of the six HIV-protease inhibitors and two non-nucleoside reverse transcriptase inhibitors in human plasma.

A selective and sensitive high-performance liquid chromatographic (HPLC) method has been developed for the determination of the six human immunodeficiency virus (HIV)-protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and the non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine) in a single run. After a liquid-liquid extraction with diethyl ether, the six protease inhibitors and the two non-nucleoside reverse transcriptase inhibitors are separated on a Stability RP18 column eluted with a gradient of acetonitrile and phosphate buffer 50 mmol/L pH 5.65. A sequential ultraviolet detection (5-minute sequence set at 240 nm for nevirapine acquisition, 22-minute sequence set at 215 nm for other antiretroviral drugs acquisition followed by a sequence set at 260 nm for internal standard acquisition) allowed for simultaneous quantitation of the six protease inhibitors, nevirapine, and efavirenz. Calibration curves were linear in the range 100 ng/mL to 10,000 ng/mL. The limit of quantitation was 50 ng/mL for all drugs except nevirapine (100 ng/mL). Average accuracy at four concentrations ranged from 88.2% to 110.9%. Both interday and intraday coefficients of variation were less than 11% for all drugs. The extraction recoveries were greater than 62%. This method is simple and shows a good specificity with respect to commonly co-prescribed drugs. This method allows accurate therapeutic monitoring of amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, efavirenz, and nevirapine.

Alkynes↗
PubMedDate not supplied

Clinical uses of non-nucleoside reverse transcriptase inhibitors.

Three non-nucleoside reverse transcriptase inhibitors (NNRTIs) are currently available for treatment of HIV-1 as part of combination antiretroviral therapy. Oral dosing is administered three times daily for delavirdine (DLV), twice daily for nevirapine (NVP), and once daily for efavirenz (EFV). Rash is a common side effect of all three NNRTIs, and early CNS side effects are also frequent with EFV. Hepatotoxicity is relatively uncommon but requires appropriate monitoring. Drug interactions mediated by the cytochrome P450 system are an important consideration when the NNRTIs are administered concomitantly with other drugs, including protease inhibitors (PIs). HIV strains with reduced susceptibility to NNRTIs can occur with a single mutation in the reverse transcriptase (RT) gene. The available NNRTIs exhibit overlapping genotypic resistance patterns, but newer agents may overcome this problem. NNRTIs have been studied in combination with nucleoside RT inhibitors for first-line HIV therapy, where they have shown at least equivalent antiviral efficacy compared with PI-based regimens over 1-2 years of therapy. NVP and EFV have also been studied as a replacement for a PI within a virologically successful regimen, with the aim of preventing or reducing PI toxicities and simplifying the dosing regimen. Such 'switch' strategies are successful for certain patients in maintaining virologic suppression for 6 months or more and result in varying degrees of improvement in PI-associated toxicities. NNRTIs may offer a benefit when included in salvage regimens for patients failing PI-based therapy, particularly in patients who have not previously been treated with NNRTIs. NVP has been shown to have a substantial favourable impact on the rate of vertical HIV-1 transmission with a simple, cost-effective regimen.

Alkynes↗
PubMed2003

Toxicity of non-nucleoside analogue reverse transcriptase inhibitors.

The non-nucleoside reverse transcriptase inhibitors (NNRTI) nevirapine (NVP), efavirenz (EFV), and delaviridine (DLV) are increasingly being used to treat HIV infection. Studies have shown excellent tolerance and efficacy and less development of virological resistance with HIV regimens that include NNRTIs. Nevertheless, abnormalities in liver enzymes are common in patients with HIV infection, and there are multiple etiologies for these abnormalities, including drug toxicity, viral hepatitis, opportunistic infections, and substance abuse. In particular, highly active antiretroviral therapy (HAART) can result in hepatotoxicity through a variety of mechanisms, such as mitochondrial toxicity, lipodystrophy syndrome, and steatohepatitis. The NNRTIs have been most frequently implicated in hypersensitivity reactions. NVP-containing HAART regimens may be more hepatotoxic than are those with EFV and DLV, at least for the first 6 weeks, although the data are still contradictory. Coinfection with hepatitis C and B viruses appears to significantly increase the risk of toxicity, and therefore all patients should be screened for viral hepatitis prior to commencing HAART. Close monitoring of transaminases is suggested in all patients commencing HAART, especially those with preexisting liver disease and coinfection with viral hepatitis.

Alkynes↗
PubMed2004

Direct, DNA pol-gamma-independent effects of nucleoside reverse transcriptase inhibitors on mitochondrial bioenergetics.

Nucleoside reverse transcriptase inhibitor (NRTI)-induced cardiomyopathy has been suggested to reflect mitochondrial targets of drug toxicity. The prevailing hypothesis is that, through structural mimicry, the NRTIs are mistaken as substrates for DNA polymerase and incorporated into replicating DNA, where they cause truncation of the elongating strand. Although there exist five forms of nuclear DNA polymerase, mitochondria possess solely DNA polymerase-gamma (pol-gamma), which is a preferred target for most NRTIs. Consequently, mitochondria are particularly susceptible to inhibition of DNA replication by the NRTIs, which is consistent with the phenotype of mitochondrial depletion and metabolic failure in affected patients. However, the DNA pol-gamma hypothesis by itself fails to explain the entire array of metabolic deficiencies associated with NRTI-induced disorders. In this article, we review the published literature regarding the direct effects of NRTIs on various mitochondrial targets and suggest the possibility that the initiating event in NRTI-induced cardiomyopathy is a direct mitochondrial toxicity rather than inhibition of mitochondrial DNA pol-gamma. The goal of this review is to encourage a discussion of the cause of NRTI-induced mitochondrial cardiomyopathy to include a fresh consideration of all possible targets and integrating pathways that are involved in establishing mitochondrial bioenergetic fidelity and metabolic capacity in the affected myocardium.

Animals↗
PubMed2002

Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors.

BACKGROUND: Some nucleoside analogue reverse transcriptase inhibitors (NRTI) may cause depletion of mitochondrial (mt) DNA in liver by inhibiting polymerase-gamma. mtDNA depletion may contribute to lactic acidosis, steatohepatitis and liver failure. OBJECTIVE: To evaluate the long-term mitochondrial toxicity of NRTI combinations. METHODS: The HepG2 human hepatoma cell line was cultivated in the presence of zalcitabine (ddC), didanosine (ddI), stavudine (d4T), lamivudine (3TC), zidovudine (ZDV) and efavirenz at concentrations equivalent to steady-state peak plasma levels (C ), and also in one-third and 10 times C. The NRTI were added to the medium alone or in combination. Control cells were incubated without any NRTI or with efavirenz. Cell growth, lactate production, intracellular lipid droplets, mtDNA and the mtDNA-encoded respiratory chain subunit COX II were monitored over a period of up to 30 days. RESULTS: Time- and dose-dependent mtDNA depletion was observed with ddC > ddI > d4T and mtDNA depletion preceded or coincided with a decline in COX II expression, a decrease in cell growth, increased lactate production and increased intracellular lipids. 3TC and efavirenz did not affect any measurement. ZDV increased lactate moderately and cell growth was inhibited, despite normal mtDNA and COX II levels. The negative effects on some measurements were more pronounced in the 3TC-ZDV and ddC-d4T combinations, than in the single-NRTI incubations. The combination of ddI-d4T was not more toxic than ddI alone. Mitochondrial damage by ZDV, d4T, ddI, and ddC did not reach steady-state by day 25. Using a Southern blot technique, mtDNA deletions were never observed. CONCLUSION: The data indicate additive or synergistic long-term mitochondrial toxicity in some NRTI combinations.

Acidosis, Lactic↗
PubMed2001

Nonnucleoside reverse transcriptase inhibitors are chemical enhancers of dimerization of the HIV type 1 reverse transcriptase.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of the HIV type 1 (HIV-1) reverse transcriptase (RT). Yeast grown in the presence of many of these drugs exhibited dramatically increased association of the p66 and p51 subunits of the HIV-1 RT as reported by a yeast two-hybrid assay. The enhancement required drug binding by RT; introduction of a drug-resistance mutation into the p66 construct negated the enhancement effect. The drugs could also induce heterodimerization of dimerization defective mutants. Coimmunoprecipitation of RT subunits from yeast lysates confirmed the induction of heterodimer formation by the drugs. In vitro-binding studies indicate that NNRTIs can bind tightly to p66 but not p51 and then mediate subsequent heterodimerization. This study demonstrates an unexpected effect of NNRTIs on the assembly of RT subunits.

Amino Acid Substitution↗