Estimation of efficacy of hiv nucleoside-analogue reverse transcriptase inhibitor (azt) via stochastic modeling

Proceedings of the 19th International Symposium on Mathematical Theory of Networks and Systems – MTNS 2010 • 5–9 July, 2010 • Budapest, Hungary Estimation of efficacy of HIV nucleoside-analogue reverse transcriptase inhibitor (AZT) via stochastic modeling Samira Khalili, James M. Monaco, and Antonios Armaou, Senior Member IEEE & Member AIChE, SIAM Abstract— In this work, the mechanisms by which nucleoside- In this study, a mechanistically informed model for the analogue reverse transcriptase inhibitors (NRTIs), the most intracellular interaction of HIV-1 and NRTIs was developed common class of drugs used in the treatment of HIV-1, exert which provides necessary tools to more accurately simulate their antiviral effects are analyzed and methods in which thoseknown mechanisms could be employed to generate mathemat- the progression of the HIV infection and its response to ical models for drug efficacy in terms of measurable physical treatment. The detailed explanation of the model and more values are identified. Drug concentration is considered as a time results can be find in [17]. The development of this type of variant parameter which depends on the drug administration mechanistic model can help guide future experimental inves- time and dosage.
tigations by highlighting the key parameters that ultimatelydetermine the drug's efficacy. The efficacy was linked with time-varying RTI triphosphate concentration from physio- In order to describe the dynamics of the HIV infection, logic data on intracellular triphosphate concentration max- causative agent of AIDS, numerous mathematical models imums and half lives, such as that collected in [15].
of varying detail have been proposed in the open liter- II. REVERSE TRANSCRIPTION PROCESS ature to capture different aspects of disease progression.
Currently, physically informed mathematical models have The reverse transcription of viral RNA to DNA initiates af- been developed for many aspects of the HIV reproductive ter attachment of virus to host and fusion of viral components cycle and the majority include drug efficacy as time-invariant into the host cytoplasm. The process of reverse transcription constants [1], [2], [3], [4]. Such mathematical models have is not linear; up to three strands, a negative sense strand and been employed to control disease progression and optimize two halves of the positive sense strand, may be transcribed at medication schedules [5], [3]. In [6], a model predictive once. The process, as described in detail in [18] and shown in control based method for determining optimal treatment figure 1, includes these steps: (1) Host-provided tRNA binds interruption of HAART was developed to schedule HIV to the primer binding site (PBS) and (-) strand transcription therapy. In [7] and [8], optimal medication strategies were begins. (2) Upon reaching the 5' end of the RNA template, scheduled for the primary stage of infection. The role of the (-) strand is transferred to the 3' end. (3) Initiation of mathematical modeling on the optimal control of HIV-1 the U(+) and D(+) strands begins as the (-) strand reaches pathogenesis was reviewed in [9].
the two purine-rich primer sites. (4) After the U(+) and the Studies such as [10], [11] use broad empirical models, as (-) strand reach the the 5' end of their respective templates, summarized by Greco, et. al. in [12]. These models estimate another strand transfer occurs.This allows each to use the the correlation between drug concentration and efficacy.
other as a template and continue transcription. (5) The ring However, no models have attempted to reflect the class- structure is opened as the (-) strand continues to the 5' end specific mechanisms by which the major types of antiretro- of the U(+) strand and the D(+) strand continues to the 5' viral drugs exert their inhibitory effect. Nucleoside analogue end of the (-) strand. (6) Transcription is complete once the RT inhibitors (NRTIs) are prodrugs and they must undergo U(-) strand displaces 100 bases of the D(+) strand to reach three enzyme-catalyzed phosphorylations before reaching the central termination site (CTS).
their active anabolite form. In the next step, the drugs must After approximately 20000 reverse-transcriptase medi- compete with natural deoxynucleotides to exert their effects.
ated nucleotide polymerization events, the complete double- This prevents easy correlation of plasma concentrations with stranded copy of viral DNA which is called a provirus is instantaneous efficacy. Still, there are techniques for quickly ready for being integrated into the host genome. During those and directly measuring the intracellular concentration of 20000 nucleotide additions, NRTIs can exert their desired NRTI triphosphates and natural dNTPs [13], [14], [15], [16].
NRTIs compete with natural nucleotides for addition into S. Khalili and A. Armaou are with the Department of Chemical Engi- the HIV reverse transcription complex. They inhibit proviral neering, Pennsylvania State University, University Park, PA-16802 production through chain termination. However, addition of Corresponding author, email: [email protected] The author grate- an NRTI molecule to the growing HIV genome does not fully acknowledges the financial support of the National Science Foun-dation Career Award # CBET 06-44519 and American Chemical Society, guarantee permanent chain termination in the intracellular Petroleum Research Fund, grant PRF # 44300-G9.
environment. HIV reverse transcriptase enzyme can also ISBN 978-963-311-370-7


S. Khalili et al. • Estimation of Efficacy of HIV Nucleoside-Analogue Reverse Transcriptase Inhibitor (AZT) via Stochastic Modeling the concentrations of free nucleotide and RT transcriptioncomplex. As such, the overall rates of nucleotide and NRTIaddition could be expressed as: rate(+dN T P ) = krl( [dN T P ][RT.DN A]) rate(+RT P ) = kirl( [RT P ][RT.DN A]) In which KD and Ki are the dissociation constants for the natural nucleotide and the drug, and krl and kirl are therespective rate constants for the rate limiting step. Equations1 and 2 can be used to calculate the probability of NRTItriphosphate addition: rate(+RT P ) Fig. 1. An outline of critical reverse transcription events. Figure reproduced rate(+RT P ) + rate(+dN T P ) from (Gotte and Li, 1999).
kirl [RTP] catalyze the reverse reaction which results in the removal of the terminal nucleotide.
A. Efficacy: measurement of drug effectiveness which is equivalent to: There are several measures used to determine the efficacy of therapy: changes in T-cell counts, log-reductions in viral KDkirl [RT P ] titers, and IC 50 [11], [12], [13]. Here, the concept of efficacy KDkirl [RT P ] + [dNT P ] outlined by Perelson et al. [1] is used. In this definition, the efficacy of an NRTI is the percentage by which it reduces Since the intracellular concentration is a function of time, the apparent rate of conversion of healthy T-cells to infected p is time dependent as well. α, the relative affinity is then: T-cells over the untreated case. This definition correlatesmost closely with drug IC 50, which is defined as the plasma concentration of drug that results in a 50% reduction in the appearance of infected cells over a set incubation period in It can be thus concluded that the probability of NRTI an in vitro culture.
addition can be expressed in terms of measurable physical Addition of NRTI triphosphate occurs by the same mech- constants. Consequently, if the concentration vs. time curves anism as addition of deoxynucleotides. Hence, there are for these two species may be predicted, then trends in two possible "reactions" in the system: natural nucleotide probability of NRTIs addition over time should be likewise addition and NRTI addition. A good first step in determining predictable. The effect of this probability on overall efficacy efficacy would be to quantify the average probability that an depends upon many additional factors, most importantly the NRTI triphosphate is added at each "vulnerable" nucleotide stability of the NRTI once included in the HIV genome.
in the genome. It is expected that this probability to be de-pendent upon three factors: the intracellular concentration of B. Stability of NRTI as a chain terminator NRTI triphosphate, the concentration of the deoxynucleotide As mentioned earlier, RT can catalyze the reaction to with which it competes, and the relative selectivity (α) of remove chain-terminating NRTIs. The stability of the Ternary the RT-Genome complex for the NRTI. The next step then is Dead End Complex that forms varies enormously between describing these quantities for the intracellular environment.
drugs. As reported by Isel et al. [23], HIV RT complexes There are numerous experiments which directly measure terminated by different NRTIs demonstrated varied results the in vivo concentration of the triphosphate products for when incubated in the presence of the next incoming nu- a variety of RTIs [13], [14], [15], [19], [20], [21]. The cleotide. Isel et al. kindly provided the data of +1 rescue same techniques that are used to determine intracellular (see [23], figure 3) for AZT which was studied in this work.
NRTI TP concentrations are also used to determine natural The raw data was used to evaluate the parameters to equation deoxynucleotide concentrations [16], [22], [21].
A(1exp(−kextt)), where A is the amplitude of the reaction The binding of nucleotide to the complex is a reversible and kext is the apparent repair rate constant.
process. Since the conformational change is significantly rate Presence of NRTIs results in the reduction in the number limiting, the concentration of nucleotide-RT complex can be of new cells that HIV can infect in a given period of time.
expressed in terms of its dissociation constant, as well as This is achieved through two mechanisms: Proceedings of the 19th International Symposium on Mathematical Theory of Networks and Systems – MTNS 2010 • 5–9 July, 2010 • Budapest, Hungary Mechanism 1: Peripheral Blood Mononuclear Cells have In which ²DC is the efficacy due to dead end complex a set lifespan in vivo, and express certain natural defense formation, p is the probability of NRTI addition each time factors that may potentially degrade the HIV RT complex.
a vulnerable base is transcribed (expressed in equations 5 If an NRTI's TDEC is stable, then the reduction in infection and 6) and B is the number of vulnerable bases in the rate might be the result of a certain fraction of HIV fusions complete genome. It is important to note that only formation being effectively arrested during reverse transcription. The of indefinitely stable TDECs (mechanism 1) contributes to apparent rate of infections decreases by the percentage the calculation of efficacy in the above equation. The effect reduction in completed reverse transcriptions.
of time delay (mechanisms 2.I and 2.II) on efficacy needs Mechanism 2: If TDECs are not stable, each addition of an NRTI to the HIV genome would still represent a There are a number of shortcomings to expression 8. As period of holdup in the reverse transcription phase, extending discussed earlier, the delay of reverse transcription (mech- the time between viral fusion and active infection. When anism 2), might be as important as permanent termina- multiple NRTI additions occur, the holdup time may exceed tion of the RT complex (mechanism 1) which can not the time it would take for the host cell to die or clear the be included in our proposed equation in a straightforward RT complex. This, also will reduce the number of cells that manner. Fortunately, stochastic simulation provides us with become infected in a given period of time. We can consider the ability of calculating the time delay associated with a two types of time delay: time delay which exceeds the life certain concentration as well as the permanent termination.
span of RNA in cytoplasm, which we define as mechanism Furthermore, since addition of NRTI is a discrete event, and 2.I, and time delay which does not exceed the life span of p(t) depends on the concentration of NRTI which changes the RNA in cytoplasm, which we define as mechanism 2.II.
with time, stochastic simulation can provide a more accurate In other words, the source of NRTI efficacy is likely due estimation of the probability of NRTI addition over the to a combination of both mechanisms (1) and (2): NRTI transcription process. The results of stochastic simulation induces a moderate delay in reverse transcription, increasing will be discussed in detail in section IV.
the chance of a viral fusion failing to produce an activelyinfected T-cell while causing those that do succeed to take III. STOCHASTIC MODEL OF REVERSE TRANSCRIPTION longer in doing so. Such a process defies reduction to a simple mathematical description, but is approachable via in An investigation of the problem might persuade one to sillico stochastic modeling of the individual events that occur wonder if the overall delay in reverse transcription resulting during reverse transcription.
from NRTI could be calculated simply by taking the expected C. Estimation of NRTI efficacy number of NRTI additions per genome and multiplying bythe expected time that each chain termination will last.
In [11], plasma time-course of drug concentration is de- Unfortunately, As discussed in section II, the reverse tran- scription is a nonlinear process. The inhibition of one strand C(T ) + t (C will not necessarily prevent the others from being elongated.
C(t) = max − C(T )) 0 ≤ t ≤ tp Cmax exp(−ω(t − tp)) tp < t < T As such, the location and time when NRTI addition occurs affects just how long it delays the entire process. The p and T represent dosing interval (administration proposed stochastic model accurately simulates the entire time) and time to peak, respectively; and ω = log(2) where process of reverse transcription on an event-by-event basis, T1/2 is plasma half life of the drug. It was assumed that the "building" the genome one base at a time with probabilistic drug concentration peaks instantaneously when the dose is addition of NRTIs followed by stochastic analysis of the taken, i.e., tp = 0.
ultimate path to chain-terminator removal. Figure 2 shows In this work, we have attempted to develop a more accurate the algorithm of the simulation. Specifically this algorithm model which considers not only changes in drug concentra- is based on Gillespie's next reaction algorithm to the RT tion, but also specific drug properties like the probability of process. The "nonlinear guideline" in figure 2 eludes to forming dead end complex. Each time the idealized NRTI choosing which strand of the DNA the simulation is currently is added to the growing HIV provirus, it is either removed transcribing. It is a sequence of events which is described in by pyrophosphorolysis or successfully forms a stable dead- section II and graphically presented in figure 1. A random end complex. Under cellular conditions, both phosphorolysis sequence was chosen from the NIH HIV sequence database and TDEC formation can be considered first-order reactions for simulation. For each drug one million simulation runs that compete for NRTI-terminated RT complexes. Thus, the were used to compute the time distributions as well as formation of a stable complex can again be calculated as a percentage of TDEC formation.
propensity function in terms of these rates, yielding someprobability pTDEC that a dead end complex will form.
IV. RESULTS AND DISCUSSIONS The overall probability of permanent elimination of the RT In this section, the simulations' results are discussed.
complex, which is equivalent to efficacy in this case, can be The reverse transcription (without considering the effect of inhibitors) is a stochastic process. As a result, the reverse 1 − ²DC = (1 − p · pTDEC)B transcription process acquires a time distribution rather than S. Khalili et al. • Estimation of Efficacy of HIV Nucleoside-Analogue Reverse Transcriptase Inhibitor (AZT) via Stochastic Modeling In Table I summary of the simulations results are pre- sented. Investigating the one million runs for each case,four different outcomes can be identified: NRTI additionswhich lead to dead end complex formation (mechanism 1), Based on the transcription recipe, choose the block (A, G, C, or T) NRTI additions which delay the process so that the overall to be transcribed time exceeds the life span of RNA (mechanism 2.I), NRTIadditions which delay the overall process but not enough toexceed the life span of RNA (mechanism 2.II), and finally no Is it a vulnerable block to the simulated NRTI addition. Although mechanism 2.II results in delaying the reverse transcription process, viral DNA will be produced Copy the block and add to the chain and eventually integrated and transcribed to generate new Calculate "p" based on Update concentration virus particles. In other words, mechanism 2.II and no NRTI Generate a random number "R1" Move to the next block addition can be considered as "unsuccessful inhibition" casesand mechanism 1 and 2.II as "successful inhibition" cases.
Consequently, we defined the successful inhibition or the overall efficacy of stochastic simulation, ²si%, as the sum of mechanism 1 (²DC%) and mechanism 2.I. ²si% is shown Add RTI to the chain.
Generate a random number "R2" in the last column in Table I.
Is R2 < p(TDEC)? EFFECT OF CONCENTRATION AND HALF LIFE ON AZT INHIBITORY Calculate the RTI dissociation time based on exponential dist. EFFECT FOR WILD TYPE VIRUS. THE OVERALL EFFICACY ²si% IN THE Advance time.
Update concentration LAST COLUMN IS THE SUM OF ²DC % AND THE PERCENT OF 2.I. NO Move to the next block NRTI ADDITION PERCENTAGE AND 2.II PERCENTAGE REPRESENT THE FAILURE OF THE NRTI TO INHIBIT REVERSE TRANSCRIPTION.
Algorithm of the stochastic simulation. p and pT DEC show the probability of NRTI addition to the chain and the probability of forming a dead end complex, respectively. "Nonlinear guideline" refers to which strand of the DNA is currently being considered as described in [18] andfigure 1.
a precise time: tRT = 221.14 min with variance of 5.48 min.
The distribution is shown in figure 3.
A. Effect of reverse transcription inhibitors on reverse tran- scription time In this study AZT which is T-analogue is simulated. The parameters used for simulation are: α = 10, k ext = 1.76 × 103[1/s], and p T DEC = 8.1%.
Although the value of affinity is significant, one should note that the concentrations of drug and the natural nu-cleotide play an important role in determining the probability It was assumed that the administration time is every eight of inclusion of NRTI in the chain. Once included in the chain, hours, and two different half lives: 2 and 4 hours were it is more beneficial if 1) the extension time is long (small investigated. As discussed before in section II-C, a longer half life means higher p and consequently higher efficacy.
ext) and 2) the probability of forming TDEC, pT DEC is Efficacy also increases with drug concentration as expected.
Half-life and the initial drug concentration are two very In order to show the effect of drug administration time as important inputs for the simulations. Because of the variety well, at, we chose a value for maximum concentration (here in reported half-life values in literature, various values were Cmax = 2) and simulated six cases: adminstration time of 4 simulated: h = 1, 2, 4[hr]. The IC50 values in literature for and 8 hours; and half lives of 1, 2, and 4 hours (the results AZT are quite similar and the value of IC50 = 10[nM] was are not shown here). It is interesting to note that when the used in the simulations. It is important to emphasize here half life is very short (comparing to at), ²si is slightly larger that Cmax, which is the maximum drug concentration at the than ²DC; however, when the half life is larger, the difference time of administration, is the input for the simulation, not between ²si and ²DC becomes significant.
the IC50. However, Cmax should be chosen considering the It is also interesting to investigate the time distribution of IC50. Six different ratios of Cmax to IC50 were simulated: reverse transcription process under treatment and compare (0.1, 0.25, 0.5, 1, 2, 4).
it with no treatment time distribution. It is important to Proceedings of the 19th International Symposium on Mathematical Theory of Networks and Systems – MTNS 2010 • 5–9 July, 2010 • Budapest, Hungary note that the TDEC forming cases were not considered VI. ACKNOWLEDGMENT in time distribution graphs. No NRTI addition cases also Financial support from NSF, CAREER Award #CBET 06- were not included in order to see the effect of time delays 44519, is gratefully acknowledged. The authors would like to more vividly. One may need to consider the TDEC and thank Dr. Isel for very helpful discussions and also providing no NRTI addition percentages with the graphs to gain an the experimental data necessary for this study.
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Pharmacological Treatment of Schizophrenia by Richard H. Hall, 1998 Drugs The primary theory of schizophrenia at the neurotransmitter level, the dopamine hypothesis, was formed as the result of an accidental, yet dramatic event in the history of the treatment of schizophrenia. In the 1940s a French surgeon, Henri Laborit, began using a drug in an effort to reduce post operative shock in his patients. Laborit found that the drug reduced patients' anxiety without impairing cognitive functioning. This finding lead French drug companies to explore similar drugs, and as a result Chlorpromazine was developed. This drug was tested on a variety of mental disorders and did not seem to have much affect on disorders such as depression, but had dramatic effects on schizophrenia. As a result the "drug revolution" in the treatment of schizophrenia was born, and the result was profound. Schizophrenic patients who had been "out of touch" from consensus reality for years, were suddenly able to function effectively in society. As we'll discuss below, the effects do not occur for all schizophrenics, and there were side effects. Nevertheless, the introduction of drugs like chlorpromazine increased practitioners' ability to treat schizophrenia more dramatically than anything before, or anything that has come sense. Like all anti-schizophrenic drugs that have since been introduced, chlorpromazine was a dopamine (DA) antagonist. Since the introduction of chlorpromazine, anti-schizophrenic drugs have improved. Primarily they have become more specific in their effect, and, as a result, the side effects have decreased. One of the first widely used drugs introduced after Chlorpromazine is called Haloperidol (that goes by the commercial name, Haldol), and it is also a dopamine antagonist. However, it has it's primary effect on one principal type of dopamine receptor, DA2 receptors. Recently another class