Effects Of Reverse Transcriptase Inhibitors Research Articles

Optimal control of combined antiretroviral therapies in an HIV infection model with cure rate and fusion effect

This paper mainly targets to deduce an optimal treatment strategy for combined antiretroviral drugs, which can maximize healthy CD4+ T cells level with minimum side effects and cost. For this purpose, we consider a within-host treatment model for the HIV infection with two controls incorporating full logistic proliferation of healthy CD4+ T cells, cure rate and fusion effect. These two controls represent the effects of reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs), respectively. The model analysis begins with proving different basic properties like non-negativity, boundedness of the model solutions and calculation of the basic reproduction number of the model under consideration. Then, stability results are obtained for HIV infection-free equilibrium point and also, a critical efficacy for the combined therapies is calculated. After that, the optimal control problem is proposed and solved numerically using a forward–backward iterative method. Finally, we obtain an optimal treatment strategy that can maximize healthy CD4+ T cells count and control the viral load, and HIV-infected CD4+ T cells count to an undetectable level resulting in improved health conditions of infected individuals.

Effects of Reverse Transcriptase Inhibitors on Proliferation, Apoptosis, and Migration in Breast Carcinoma Cells.

High telomerase activity in human breast cancer is associated with aggressive tumors resulting in decreased survival. Recent studies have shown that telomerase inhibitors may display anticancer properties in some human cancer cell lines. In the present study, we examined the effects of 4 reverse transcriptase inhibitors (RTIs), used for the treatment of HIV; Abacavir (AC), Lamivudine (LV), Stavudine (SV), and Tenofovir (TF) on proliferation, apoptosis, and migration in the normal human mammary epithelial cell line, hTERT-HME1, and the human breast cancer cell line, MCF-7. Cells were treated with AC, LV, SV, or TF alone or in combination with paclitaxel (PAC), a known drug used to treat breast cancer. Conduct of the thiazolyl blue tetrazolium bromide assay demonstrated that AC, SV, and TF had stronger cytotoxic effects on MCF-7 cells than in hTERT-HME1 cells. The combined treatment of RTIs and PAC caused high rates of cell death in MCF-7 and low rates of cell death in HTERT-HME1 by apoptosis. The percentages of apoptotic cells in the treatment of AC and SV in combination with PAC for 48 and 72 hours were higher than PAC. Significantly increased apoptosis and decreased migration levels were found in MCF-7 cells treated with AC and co-treatment of AC+PAC or SV+PAC than HME1 cells. These treatments can also prevent migration capacity more than PAC. Therefore, a combination strategy based on telomerase inhibitors such as AC or SV and anticancer drugs may be more effective in the treatment of certain breast cancers.

Global stability analysis of HIV-1 infection model with three time delays

Mathematical model for the effect of reverse transcriptase inhibitor on the dynamics of HIV-1 infection model with three delays is proposed and analyzed. We begin this model with proving the positivity and boundedness of the solution. We analyze the stability of the viral free steady state and the infected steady state of the system. Also we have carried out bifurcation analysis along with an estimated length of delay to preserve the stability behaviour. By developing a few Lyapunov functionals, we obtain conditions ensuring global stability of steady states. Numerical simulations are carried out to explain the mathematical conclusions.

Potential for simplification of HIV treatment with boosted protease inhibitor monotherapy

Previous studies have evaluated the simplification of HIV treatment with ritonavir-boosted protease inhibitor monotherapy, demonstrating acceptable efficacy and advantages such as avoidance of the adverse effects of reverse transcriptase inhibitors. To achieve the best results, patients should be appropriately selected for this therapy. The purpose of this study was to estimate the proportion of HIV patients suitable for boosted protease inhibitor monotherapy according to clinical trial criteria. Setting The study was conducted in the outpatient hospital pharmacy service of the Complejo Hospitalario de Navarra in northern Spain. A retrospective analysis was performed on data from 635 adults on antiretroviral therapy. The eligibility criteria were: (1) >18 years of age; (2) prior triple-drug antiretroviral regimen; (3) durability of current treatment >18 months; (4) viral load <400 copies/mL over the 18 months before evaluation and <50 copies/mL over the last 6 months; (5) CD4 count ≥250 cells/μL; (6) CD4 count nadir >100 cells/μL; (7) no previous virological failure under prior protease inhibitor-based regimen; (8) absence of co-infection with hepatitis B virus; (9) absence of HIV-related neurological disease; and (10) adherence >95 %. The average cost of the current treatment was calculated for patients who met all criteria, as well as the potential economic impact of simplification to monotherapy. Number of patients meeting all criteria for simplification to monotherapy according to clinical trial standards. One hundred and three patients (16.5 %) met the clinical trial criteria for protease inhibitor monotherapy. One hundred and fifty patients (24 %) failed to fulfil only one of the conditions. Fifty-four percent of the patients who met all of the criteria had been treated for more than 10 years. The average saving per patient per year was <euro>2,850-<euro>3,400. This treatment strategy represents a realistic, albeit minority, option. Fulfilment of the above conditions should be the basis for simplification to protease inhibitor monotherapy, though the final decision depends on clinical criteria and patient preferences assessed by the attending physician. Further studies are needed to confirm long-term safety and efficacy.

Effect of reverse transcriptase inhibitors on LINE-1 and Ty1 reverse transcriptase activities and on LINE-1 retrotransposition

BackgroundLINE-1s (L1, Long Interspersed Element-1) are the most abundant autonomous non-LTR retrotransposons in the human genome and replicate by reverse transcription of an RNA intermediate. Full-length L1 encodes two open reading frames (ORF1, ORF2) and ORF2 has reverse transcriptase activity.ResultsHere we expressed human L1 RT in E. coli and the purified protein displayed the same RT activity as that of ORF2p expressed in insect cells. We tested the effect of different reverse transcriptase inhibitors on L1 RT and found that all four tested nucleoside inhibitors efficiently inhibited L1 RT activity competitively. The Ki values of NRTIs were calculated (AZTTP, 16.4 ± 4.21 nM; d4TTP, 0.73 ± 0.22 nM; ddCTP, 0.72 ± 0.16 nM; 3TCTP, 12.9 ± 2.07 nM). L1 RT was less sensitive to non-nucleoside reverse transcriptase inhibitors, among these nevirapine had no effect, even at concentrations up to 500 μM. We also examined the effect of RT inhibitors on L1 retrotransposition efficiency in vivo using a cell-based retrotransposition assay. Similarly, all analog inhibitors decreased L1 retrotransposition frequency with different potencies whereas nevirapine had little or no effect on L1 retrotransposition. For comparison, we also tested the same inhibitors to highly purified RT of an LTR-retrotransposon (Ty1) and found it was less sensitive to NRTIs than L1 RT and has the same inhibition profile as L1 RT to NNRTIs.ConclusionsThese data indicate that bacterially expressed L1 RT is an active reverse transcriptase sensitive to nucleoside RT inhibitors but not to non-nucleoside inhibitors.

Reverse transcriptase activity in psoriatic lesions: effects of reverse transcriptase inhibitors on keratinocyte proliferation and differentiation

About half of the human genome is composed of ancient transposable elements that integrated the genome through out the evolution. In order to evaluate whether retroelements could be active in the psoriatic lesion, we 1/quantified endogenous reverse transcriptase (RT) activity, 2/localised RT-expressing cells 3/evaluated the effects of RT inhibitors on keratinocyte proliferation and differentiation in a skin culture model. An increased RT activity was detected in protein extracts from lesional psoriatic skin when compared to normal skin (mean Mn2+-dependent RT activity 191 ± 118 μU/ml (n = 24) vs 71 ± 78 μU/ml (n = 17) and mean Mg2+-dependent RT activity 7.3 ± 4.3 mg/ml (n = 15) vs 2.3 ± 1.93 mg/ml (n = 15); p = 0.0048 and p = 0.0009, respectively). Sera and plasma from healthy and psoriatic individuals were all negative. By anti-RT antibody staining, we detected few dermal positive cells in normal skin sections (n = 10) as in non-lesional psoriatic skin (n = 10). In contrast, in the lesional skin (n = 20), the granular layer was intensely stained as were Munro's abscesses. In addition, a subset of inflammatory cells was also positive. In order to evaluate the effects of two RT inhibitors, AZT and Efavirenz, on keratinocyte proliferation and differentiation, we first confirmed the expression of RT proteins in the granular layer of in vitro skin culture. We observed that Efavirenz at 10-5M potently reduced cell proliferation and hyperkeratosis while AZT had little or no effect on keratinocyte differentiation. These results support that endogenous retroelements are active in the psoriatic lesion and that they also participate in the control of keratinocyte proliferation and differentiation.

Reverse Transcriptase Inhibitors Alter Uncoupling Protein-1 and Mitochondrial Biogenesis in Brown Adipocytes

Human adipose depots contain remnant brown adipocytes interspersed among white adipocytes, and disturbances of brown with respect to white adipocyte biology have been implicated in highly active antiretroviral therapy (HAART)-induced lipomatosis. Brown adipocytes express the uncoupling protein-1 (UCP1) and contain a large number of mitochondria, potential targets of HAART toxicity. The aim of this study was to evaluate the effects of reverse transcriptase inhibitors (RTIs) on primary brown adipocytes differentiated in culture. We analysed the effects of RTIs, nucleoside analogues (NRTIs: stavudine, zidovudine, didanosine and lamivudine) and non-nucleoside analogues (NNRTIs: nevirapine and efavirenz), on differentiation, mitochondrial biogenesis and gene expression in brown adipocytes. None of the NRTIs altered brown adipocyte differentiation whereas NNTRIs had differing effects. Efavirenz blocked lipid deposition and expression of adipose marker genes but nevirapine induced lipid accumulation and adipose gene expression, promoted mitochondrial biogenesis and increased UCP1. Stavudine, zidovudine and didanosine reduced mitochondrial DNA (mtDNA) content. However, mitochondrial genome expression was only impaired in didanosine-treated adipocytes. Stavudine, but not zidovudine, induced expression of the mitochondrial transcription factors and this may explain compensatory mechanisms for the depletion of mtDNA by up-regulating mtDNA transcription. Stavudine caused a specific induction of UCP1 gene expression through direct interaction with a retinoic acid-dependent pathway. Specific disturbances in brown adipocytes in adipose depots may contribute to HAART-induced lipomatosis. Mitochondrial depletion does not appear to be the only mechanism explaining adverse effects in brown adipocytes because there is evidence of compensatory mechanisms that maintain mtDNA expression, and the expression of the UCP1 gene is specifically altered.

Drug resistance in an immunological model of HIV-1 infection with impulsive drug effects

We consider an SIR-type model of immunological behaviour for HIV dynamics, including the effects of reverse transcriptase inhibitors and other drugs which prevent cellular infection. We use impulsive differential equations to model drug behaviour. We classify different regimes according to whether the drug efficacy is negligible, intermediate or high. We consider two strains of the virus: a wild-type strain that can be controlled by both intermediate and high drug concentrations, and a mutant strain that can only be controlled by high drug concentrations. Drug regimes may take trajectories through one, two or all three regimes, depending on the dosage and the dosing schedule. We demonstrate that drug resistance arises at both intermediate and high drug levels. At low drug levels resistance does not emerge, but the total T cell count is proven to be significantly lower than in the disease-free state. At intermediate drug levels, drug resistance is guaranteed to emerge. At high drug levels, either the drug-resistant strain will dominate or, in the absence of longer-lived reservoirs of infected cells, both viral sub-populations will be cleared. In the latter case the immune system is maintained by a population of T cells which have absorbed sufficient quantities of the drug to prevent infection by even the drug-resistant strain. We provide estimates of a range of dosages and dosing schedules which would, if physiologically tolerable, theoretically eliminate free virus in this system. Our results predict that to control viral load, decreasing the interval between doses is more effective than increasing the dose.

Nature of equilibria and effects of drug treatments in some simple viral population dynamical models

We examine some simple mathematical models which have been recently employed to predict the evolution of population dynamical systems involving virus particles. They include: (1) A general two-component antibody-viral system; (2) A simplified two-component model for HIV-1 dynamics (3) An HIV-1 three-component model including virions and (4) A four-component HIV-1 dynamical model which includes both latently and actively infected cells. For each system we find equilibrium points and analyse their local stability properties in order to obtain a global phase portrait. Analytical methods are complemented with numerical solutions. In all four models there are at most two equilibrium points for physically meaningful values of the variables. As the viral growth rate parameter increases through a critical value, a transcritical bifurcation occurs. One critical point (P1) is always found at zero viral or infected cell levels and non-zero antibody or uninfected cell levels. For parameter values in their usual ranges, P1 is either an asymptotically stable node or a saddle point. When the critical point P2 occurs at biologically meaningful values, it is either an asymptotically stable node or an asymptotically stable spiral point. For all three HIV-1 models, the values of the parameters at which P2 makes a transition to physically meaningful values are precisely those at which P1 changes from an asymptotically stable node to an unstable saddle point. The global pictures for all four models are similar and examples are represented graphically. No limitcycle solutions were found in any of the models for parameter values in their usual ranges. In the four-component HIV-1 model, the effects of varying each parameter are found and conditions under which P2 changes from spiral point to node are investigated numerically. The effects of reverse transcriptase inhibitors and protease inhibitors, two classes of drugs used to treat HIV-1 infection, are examined in the three-component model for early HIV-1 dynamics.

Nature of equilibria and effects of drug treatments in some simple viral population dynamical models

We examine some simple mathematical models which have been recently employed to predict the evolution of population dynamical systems involving virus particles. They include: (1) A general two-component antibody-viral system; (2) A simplified two-component model for HIV-1 dynamics (3) An HIV-1 three-component model including virions and (4) A four-component HIV-1 dynamical model which includes both latently and actively infected cells. For each system we find equilibrium points and analyse their local stability properties in order to obtain a global phase portrait. Analytical methods are complemented with numerical solutions. In all four models there are at most two equilibrium points for physically meaningful values of the variables. As the viral growth rate parameter increases through a critical value, a transcritical bifurcation occurs. One critical point (P1) is always found at zero viral or infected cell levels and non-zero antibody or uninfected cell levels. For parameter values in their usual ranges, P1 is either an asymptotically stable node or a saddle point. When the critical point P2 occurs at biologically meaningful values, it is either an asymptotically stable node or an asymptotically stable spiral point. For all three HIV-1 models, the values of the parameters at which P2 makes a transition to physically meaningful values are precisely those at which P1 changes from an asymptotically stable node to an unstable saddle point. The global pictures for all four models are similar and examples are represented graphically. No limitcycle solutions were found in any of the models for parameter values in their usual ranges. In the four-component HIV-1 model, the effects of varying each parameter are found and conditions under which P2 changes from spiral point to node are investigated numerically. The effects of reverse transcriptase inhibitors and protease inhibitors, two classes of drugs used to treat HIV-1 infection, are examined in the three-component model for early HIV-1 dynamics.

Effects of reverse transcriptase inhibitors on telomerase activity in human choriocarcinoma cell lines

Effects of reverse transcriptase inhibitors on telomerase activity in human choriocarcinoma cell lines

Effects of reverse transcriptase inhibitors on telomere length and telomerase activity in two immortalized human cell lines.

The ribonucleoprotein telomerase, a specialized cellular reverse transcriptase, synthesizes one strand of the telomeric DNA of eukaryotes. We analyzed telomere maintenance in two immortalized human cell lines: the B-cell line JY616 and the T-cell line Jurkat E6-1, and determined whether known inhibitors of retroviral reverse transcriptases could perturb telomere lengths and growth rates of these cells in culture. Dideoxyguanosine (ddG) caused reproducible, progressive telomere shortening over several weeks of passaging, after which the telomeres stabilized and remained short. However, the prolonged passaging in ddG caused no observable effects on cell population doubling rates or morphology. Azidothymidine (AZT) caused progressive telomere shortening in some but not all T- and B-cell cultures. Telomerase activity was present in both cell lines and was inhibited in vitro by ddGTP and AZT triphosphate. Prolonged passaging in arabinofuranyl-guanosine, dideoxyinosine (ddI), dideoxyadenosine (ddA), didehydrothymidine (d4T), or phosphonoformic acid (foscarnet) did not cause reproducible telomere shortening or decreased cell growth rates or viabilities. Combining AZT, foscarnet, and/or arabinofuranyl-guanosine with ddG did not significantly augment the effects of ddG alone. Strikingly, with or without inhibitors, telomere lengths were often highly unstable in both cell lines and varied between parallel cell cultures. We propose that telomere lengths in these T- and B-cell lines are determined by both telomerase and telomerase-independent mechanisms.