skip to main content

Title: Modeling the Effects of Morphine-Altered Virus Specific Antibody Responses on HIV/SIV Dynamics

Drugs of abuse, such as opiates, have been widely associated with enhancing HIV replication, accelerating disease progression and diminishing host-immune responses, thereby making it harder to effectively manage HIV infection. It is thus important to study the effects of drugs of abuse on HIV-infection and immune responses. Here, we develop mathematical models that incorporate the effects of morphine-altered antibody responses on HIV/SIV dynamics. Based on fitting the model to experimental data from simian immunodeficiency virus (SIV) infections in control and morphine-addicted macaques, we found that two of the most significant effects of virus specific antibodies are neutralizing viral particles and enhancing viral clearance. Using our model, we quantified how morphine alters virus-specific antibody responses, and how this alteration affects the key components of virus dynamics such as infection rate, virus clearance, viral load, CD4+T cell count, and CD4+T cell loss in SIV-infected macaques under conditioning with morphine. We found that in a subpopulation of SIV-infected morphine addicted macaques, the presence of drugs of abuse may cause significantly diminished antibody responses, resulting in more severe infection with increased SIV infectivity, a decreased viral clearance rate, increased viral load, and higher CD4+T cell loss.

; ; ;
Publication Date:
Journal Name:
Scientific Reports
Nature Publishing Group
Sponsoring Org:
National Science Foundation
More Like this
  1. In this paper, we present a multi-scale co-affection model of HIV infection and opioid addiction. The population scale epidemiological model is linked to the within-host model which describes the HIV and opioid dynamics in a co-affected individual. CD4 cells and viral load data obtained from morphine addicted SIV-infected monkeys are used to validate the within-host model. AIDS diagnoses, HIV death and opioid mortality data are used to fit the between-host model. When the rates of viral clearance and morphine uptake are fixed, the within-host model is structurally identifiable. If in addition the morphine saturation and clearance rates are also fixed the model becomes practical identifiable. Analytical results of the multi-scale model suggest that in addition to the disease-addiction-free equilibrium, there is a unique HIV-only and opioid-only equilibrium. Each of the boundary equilibria is stable if the invasion number of the other epidemic is below one. Elasticity analysis suggests that the most sensitive number is the invasion number of opioid epidemic with respect to the parameter of enhancement of HIV infection of opioid-affected individual. We conclude that the most effective control strategy is to prevent opioid addicted individuals from getting HIV, and to treat the opioid addiction directly and independently frommore »HIV.

    « less
  2. An effective vaccine that can protect against HIV infection does not exist. A major reason why a vaccine is not available is the high mutability of the virus, which enables it to evolve mutations that can evade human immune responses. This challenge is exacerbated by the ability of the virus to evolve compensatory mutations that can partially restore the fitness cost of immune-evading mutations. Based on the fitness landscapes of HIV proteins that account for the effects of coupled mutations, we designed a single long peptide immunogen comprising parts of the HIV proteome wherein mutations are likely to be deleterious regardless of the sequence of the rest of the viral protein. This immunogen was then stably expressed in adenovirus vectors that are currently in clinical development. Macaques immunized with these vaccine constructs exhibited T-cell responses that were comparable in magnitude to animals immunized with adenovirus vectors with whole HIV protein inserts. Moreover, the T-cell responses in immunized macaques strongly targeted regions contained in our immunogen. These results suggest that further studies aimed toward using our vaccine construct for HIV prophylaxis and cure are warranted.

  3. Regoes, Roland R. (Ed.)
    While highly active antiretroviral therapy (HAART) is successful in controlling the replication of Human Immunodeficiency Virus (HIV-1) in many patients, currently there is no cure for HIV-1, presumably due to the presence of reservoirs of the virus. One of the least studied viral reservoirs is the brain, which the virus enters by crossing the blood-brain barrier (BBB) via macrophages, which are considered as conduits between the blood and the brain. The presence of HIV-1 in the brain often leads to HIV associated neurocognitive disorders (HAND), such as encephalitis and early-onset dementia. In this study we develop a novel mathematical model that describes HIV-1 infection in the brain and in the plasma coupled via the BBB. The model predictions are consistent with data from macaques infected with a mixture of simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV). Using our model, we estimate the rate of virus transport across the BBB as well as viral replication inside the brain, and we compute the basic reproduction number. We also carry out thorough sensitivity analysis to define the robustness of the model predictions on virus dynamics inside the brain. Our model provides useful insight into virus replication within the brain and suggestsmore »that the brain can be an important reservoir causing long-term viral persistence.« less
  4. Summary

    Mathematical modelling of human immunodeficiency virus (HIV) dynamics has played an important role in acquired immune deficiency syndrome research. Deterministic dynamic models have been developed to study the viral dynamic process for understanding the pathogenesis of HIV type 1 infection and antiviral treatment strategies. We propose a new multistage estimation procedure which uses data, HIV viral load and CD4+ T-cell counts, from an acquired immune deficiency syndrome clinical study, to estimate the parameters in a long-term HIV dynamic model containing both constant and time varying parameters. Simulation studies and a real data application show that the methods proposed are efficient and appropriate to estimate both constant and time varying parameters in long-term HIV dynamic models.

  5. The dynamic nature of the SIV population during disease progression in the SIV/macaque model of AIDS and the factors responsible for its behavior have not been documented, largely owing to the lack of sufficient spatial and temporal sampling of both viral and host data from SIV-infected animals. In this study, we detail Bayesian coalescent inference of the changing collective intra-host viral effective population size ( N e ) from various tissues over the course of infection and its relationship with what we demonstrate is a continuously changing immune cell repertoire within the blood. Although the relative contribution of these factors varied among hosts and time points, the adaptive immune response best explained the overall periodic dynamic behavior of the effective virus population. Data exposing the nature of the relationship between the virus and immune cell populations revealed the plausibility of an eco-evolutionary mathematical model, which was able to mimic the large-scale oscillations in N e through virus escape from relatively few, early immunodominant responses, followed by slower escape from several subdominant and weakened immune populations. The results of this study suggest that SIV diversity within the untreated host is governed by a predator-prey relationship, wherein differing phases of infection aremore »the result of adaptation in response to varying immune responses. Previous investigations into viral population dynamics using sequence data have focused on single estimates of the effective viral population size ( N e ) or point estimates over sparse sampling data to provide insight into the precise impact of immune selection on virus adaptive behavior. Herein, we describe the use of the coalescent phylogenetic frame- work to estimate the relative changes in N e over time in order to quantify the relationship with empirical data on the dynamic immune composition of the host. This relationship has allowed us to expand on earlier simulations to build a predator-prey model that explains the deterministic behavior of the virus over the course of disease progression. We show that sequential viral adaptation can occur in response to phases of varying immune pressure, providing a broader picture of the viral response throughout the entire course of progression to AIDS.« less