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Modeling the Effects of Morphine on Simian Immunodeficiency Virus Dynamics

View Article: PubMed Central - PubMed

ABSTRACT

Complications of HIV-1 infection in individuals who utilize drugs of abuse is a significant problem, because these drugs have been associated with higher virus replication and accelerated disease progression as well as severe neuropathogenesis. To gain further insight it is important to quantify the effects of drugs of abuse on HIV-1 infection dynamics. Here, we develop a mathematical model that incorporates experimentally observed effects of morphine on inducing HIV-1 co-receptor expression. For comparison we also considered viral dynamic models with cytolytic or noncytolytic effector cell responses. Based on the small sample size Akaike information criterion, these models were inferior to the new model based on changes in co-receptor expression. The model with morphine affecting co-receptor expression agrees well with the experimental data from simian immunodeficiency virus infections in morphine-addicted macaques. Our results show that morphine promotes a target cell subpopulation switch from a lower level of susceptibility to a state that is about 2-orders of magnitude higher in susceptibility to SIV infection. As a result, the proportion of target cells with higher susceptibility remains extremely high in morphine conditioning. Such a morphine-induced population switch not only has adverse effects on the replication rate, but also results in a higher steady state viral load and larger CD4 count drops. Moreover, morphine conditioning may pose extra obstacles to controlling viral load during antiretroviral therapy, such as pre-exposure prophylaxis and post infection treatments. This study provides, for the first time, a viral dynamics model, viral dynamics parameters, and related analytical and simulation results for SIV dynamics under drugs of abuse.

No MeSH data available.


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Predicted effects of morphine on antiretroviral therapy.Early ART is initiated 14 days post infection (left) and late ART is initiated 200 days post infection (right). The solid lines represent the control group and the dotted lines represent the morphine group. Two different ART efficacies, 0.6 (medium), and 0.95 (high), are simulated. Parameters given in Table 2 are used for model simulations.
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pcbi.1005127.g006: Predicted effects of morphine on antiretroviral therapy.Early ART is initiated 14 days post infection (left) and late ART is initiated 200 days post infection (right). The solid lines represent the control group and the dotted lines represent the morphine group. Two different ART efficacies, 0.6 (medium), and 0.95 (high), are simulated. Parameters given in Table 2 are used for model simulations.

Mentions: Significant effects of morphine can also be seen in post infection antiretroviral therapy (ART) as demonstrated by model simulations with early ART initiation (14 days post infection) and late ART initiation (200 days post infection) (Fig 6). Whether ART can control viral load or not depends upon the efficacy of ART. While the high ART efficacy, ε = 0.95, can successfully control the virus in both groups, the viral suppression is more effective in the control group than in the morphine group in general (Fig 6). Most importantly, for intermediate level of ART efficacy (for example, 60% in our simulation), ART can suppress the viral load in the control group, but fails to suppress in the morphine group with both early and late ART initiation (Fig 6). Note that the value of ε = 0.95 and 0.6 are taken only for demonstration purposes. While current combination ARTs are highly efficacious, it is possible to have lower efficacies due to lack of compliance or emergence of resistance. Further, some combination therapies have been estimated to have efficacies in the 60 to 70% range [63].


Modeling the Effects of Morphine on Simian Immunodeficiency Virus Dynamics
Predicted effects of morphine on antiretroviral therapy.Early ART is initiated 14 days post infection (left) and late ART is initiated 200 days post infection (right). The solid lines represent the control group and the dotted lines represent the morphine group. Two different ART efficacies, 0.6 (medium), and 0.95 (high), are simulated. Parameters given in Table 2 are used for model simulations.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5036892&req=5

pcbi.1005127.g006: Predicted effects of morphine on antiretroviral therapy.Early ART is initiated 14 days post infection (left) and late ART is initiated 200 days post infection (right). The solid lines represent the control group and the dotted lines represent the morphine group. Two different ART efficacies, 0.6 (medium), and 0.95 (high), are simulated. Parameters given in Table 2 are used for model simulations.
Mentions: Significant effects of morphine can also be seen in post infection antiretroviral therapy (ART) as demonstrated by model simulations with early ART initiation (14 days post infection) and late ART initiation (200 days post infection) (Fig 6). Whether ART can control viral load or not depends upon the efficacy of ART. While the high ART efficacy, ε = 0.95, can successfully control the virus in both groups, the viral suppression is more effective in the control group than in the morphine group in general (Fig 6). Most importantly, for intermediate level of ART efficacy (for example, 60% in our simulation), ART can suppress the viral load in the control group, but fails to suppress in the morphine group with both early and late ART initiation (Fig 6). Note that the value of ε = 0.95 and 0.6 are taken only for demonstration purposes. While current combination ARTs are highly efficacious, it is possible to have lower efficacies due to lack of compliance or emergence of resistance. Further, some combination therapies have been estimated to have efficacies in the 60 to 70% range [63].

View Article: PubMed Central - PubMed

ABSTRACT

Complications of HIV-1 infection in individuals who utilize drugs of abuse is a significant problem, because these drugs have been associated with higher virus replication and accelerated disease progression as well as severe neuropathogenesis. To gain further insight it is important to quantify the effects of drugs of abuse on HIV-1 infection dynamics. Here, we develop a mathematical model that incorporates experimentally observed effects of morphine on inducing HIV-1 co-receptor expression. For comparison we also considered viral dynamic models with cytolytic or noncytolytic effector cell responses. Based on the small sample size Akaike information criterion, these models were inferior to the new model based on changes in co-receptor expression. The model with morphine affecting co-receptor expression agrees well with the experimental data from simian immunodeficiency virus infections in morphine-addicted macaques. Our results show that morphine promotes a target cell subpopulation switch from a lower level of susceptibility to a state that is about 2-orders of magnitude higher in susceptibility to SIV infection. As a result, the proportion of target cells with higher susceptibility remains extremely high in morphine conditioning. Such a morphine-induced population switch not only has adverse effects on the replication rate, but also results in a higher steady state viral load and larger CD4 count drops. Moreover, morphine conditioning may pose extra obstacles to controlling viral load during antiretroviral therapy, such as pre-exposure prophylaxis and post infection treatments. This study provides, for the first time, a viral dynamics model, viral dynamics parameters, and related analytical and simulation results for SIV dynamics under drugs of abuse.

No MeSH data available.


Related in: MedlinePlus