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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.

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Schematic diagram of the model.The model contains two subpopulations, Tl and Th of target cells, with low and high susceptibilities to infection. Cells within these populations can switch susceptibilities with rates r and q, respectively. The target cells are infected, upon contact with virus, V, at rates βl and βh, respectively, and become productively infected cells, I.
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pcbi.1005127.g001: Schematic diagram of the model.The model contains two subpopulations, Tl and Th of target cells, with low and high susceptibilities to infection. Cells within these populations can switch susceptibilities with rates r and q, respectively. The target cells are infected, upon contact with virus, V, at rates βl and βh, respectively, and become productively infected cells, I.

Mentions: A schematic diagram of the model is presented in Fig 1. We assume that target cells are generated at a constant rate λ and have a per capita net loss rate d, which is the difference between the rate of loss from cell death and rate of gain due to cell division. For simplicity, we assume that newly generated target cells are all in the Tl-group. The rate of transition from Tl to Th is denoted by r, while that from Th to Tl is denoted by q. Target cells, Tl and Th, become productively infected cells, I, upon contact with free virus, V, at rates βl and βh, respectively. The parameters δ, p, and c are the rate constants of infected cell loss, virus production by infected cells, and virus clearance, respectively. The model can be described by the following set of equations:dTldt=λ+qTh−dTl−rTl−βlVTl,Tl(0)=Tl0,(1)dThdt=rTl−dTh−βhVTh−qTh,Th(0)=Th0,(2)dIdt=βlVTl+βhVTh−δI,I(0)=I0,(3)dVdt=pI−cV,V(0)=V0.(4)


Modeling the Effects of Morphine on Simian Immunodeficiency Virus Dynamics
Schematic diagram of the model.The model contains two subpopulations, Tl and Th of target cells, with low and high susceptibilities to infection. Cells within these populations can switch susceptibilities with rates r and q, respectively. The target cells are infected, upon contact with virus, V, at rates βl and βh, respectively, and become productively infected cells, I.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1005127.g001: Schematic diagram of the model.The model contains two subpopulations, Tl and Th of target cells, with low and high susceptibilities to infection. Cells within these populations can switch susceptibilities with rates r and q, respectively. The target cells are infected, upon contact with virus, V, at rates βl and βh, respectively, and become productively infected cells, I.
Mentions: A schematic diagram of the model is presented in Fig 1. We assume that target cells are generated at a constant rate λ and have a per capita net loss rate d, which is the difference between the rate of loss from cell death and rate of gain due to cell division. For simplicity, we assume that newly generated target cells are all in the Tl-group. The rate of transition from Tl to Th is denoted by r, while that from Th to Tl is denoted by q. Target cells, Tl and Th, become productively infected cells, I, upon contact with free virus, V, at rates βl and βh, respectively. The parameters δ, p, and c are the rate constants of infected cell loss, virus production by infected cells, and virus clearance, respectively. The model can be described by the following set of equations:dTldt=λ+qTh−dTl−rTl−βlVTl,Tl(0)=Tl0,(1)dThdt=rTl−dTh−βhVTh−qTh,Th(0)=Th0,(2)dIdt=βlVTl+βhVTh−δI,I(0)=I0,(3)dVdt=pI−cV,V(0)=V0.(4)

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