Mathematical modeling of viral kinetics under immune control during primary HIV-1 infection

Burg, David; Liang, Rong; Neumann, Avidan U.; Dahari, Harel

doi:10.1016/j.jtbi.2009.04.010

Cited by 82 publications

(61 citation statements)

References 37 publications

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“…Ϫ9 ml RNA copies Ϫ1 day Ϫ1 ), and mean infected cell death rate (␦ ϭ 2.05 ϫ 10 Ϫ1 day Ϫ1 ) were consistent with previous human and macaque studies (34,35,36,32,37,38,39,40,41). The value for the mean saturation rate n was found to be 5.05 ϫ 10 4 RNA copies ml Ϫ1 , implying a relatively high viral load threshold for the indirect effect to saturate.…”

Section: Ified Cd4supporting

confidence: 87%

The Majority of CD4 ⁺ T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells

Matrajt

Younan

Kiem

et al. 2014

J Virol

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Untreated human immunodeficiency virus (HIV) infection is characterized by depletion of CD4؉ T cells, ultimately leading to the impairment of host immune defenses and death. HIV-infected CD4 ؉ T cells die from direct virus-induced apoptosis and CD8 T-cell-mediated elimination, but a broader and more profound depletion occurs in uninfected CD4؉ T cells via multiple indirect effects of infection. We fit mathematical models to data from experiments that tested an HIV eradication strategy in which five macaques with a proportion of CD4 ؉ T cells resistant to simian-human immunodeficiency virus (SHIV) entry were challenged with SHIV89.6P, a highly pathogenic dual-tropic chimeric SIV-HIV viral strain that results in rapid loss of both SHIV-susceptible and SHIV-resistant CD4 ؉ T cells. Our results suggest that uninfected (bystander) cell death accounts for the majority of CD4 ؉ T-lymphocyte loss, with at least 60% and 99% of CD4 ؉ T cell death occurring in uninfected cells during acute and established infection, respectively. Mechanisms to limit the profound indirect killing effects associated with HIV infection may be associated with immune preservation and improved long-term survival. IMPORTANCE HIV infection induces a massive depletion of CD4 ؉ T cells, leading to profound immunodeficiency, opportunistic infections, and eventually death. While HIV induces apoptosis (programmed cell death) by directly entering and replicating in CD4؉ T cells, uninfected CD4 ؉ T cells also undergo apoptosis due to ongoing toxic inflammation in the region of infection. In this paper, we use mathematical models in conjunction with data from simian-human immunodeficiency virus SHIV89.6P infection in macaques (a model of HIV infection in humans) to estimate the percentage of cell death that occurs in uninfected cells during the initial period of infection. We reveal that the vast majority of cell death occurs in these cells, which are not infected. The "bystander effects" that lead to enormous reductions in the number of uninfected CD4 ؉ T cells may be a target for future interventions that aim to limit the extent of damage caused by HIV.

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Section: Ified Cd4supporting

confidence: 87%

The Majority of CD4 ⁺ T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells

Matrajt

Younan

Kiem

et al. 2014

J Virol

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“…For simplicity, we constructed a model that assumed clearance of oral shedding results from a mounting cytolytic response based on a saturated process [25]. For details, see Equation S2 in Supplementary Methods and Supplementary Table S2.…”

Section: Mathematical Modeling Of the Oral Immune Response To CMVmentioning

confidence: 99%

Dynamics of Persistent Oral Cytomegalovirus Shedding During Primary Infection in Ugandan Infants

Mayer¹,

Matrajt²,

Casper³

et al. 2016

J Infect Dis.

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Cytomegalovirus (CMV) infection occurs frequently in young children, who, when infected, are then a major source of transmission. Oral CMV shedding by 14 infants with primary infection was comprehensively characterized using quantitative polymerase chain reaction weekly for ≥9 months. Three phases of oral shedding were identified: expansion, transition, and clearance. Viral expansion occurred over a median of 7 weeks, with a median doubling time of 3 days. During the transition phase, expansion slowed over a median of 6 weeks before peak viral load was reached. Clearance was slow (22-day median half-life), and shedding did not resolve during observation for any infant. Mathematical modeling demonstrated that prolonged oral CMV expansion is explained by a low within-host reproduction number (median, 1.63) and a delayed immune response that only decreases the infected cell half-life by 44%. Thus, the prolonged oral CMV shedding observed during primary infection can be explained by slow viral expansion and inefficient immunologic control.Keywords. epidemiology; cytomegalovirus; transmission; mathematical model; immunology; theoretical biology.Worldwide, most primary cytomegalovirus (CMV) infections occur during early childhood, through the oral route [1]. Infected infants shed CMV orally at high, persistent levels [2-6] and are a major source of transmission, including to pregnant women, which contributes to congenital infection [3,[7][8][9]. Viral dynamics during primary infection are governed by properties of viral infectivity and the immune response. A detailed study of these processes could identify immunologic thresholds necessary for effective vaccination. Here, we use mathematical models to describe oral shedding dynamics during primary CMV infection in a cohort of Ugandan infants. MATERIALS AND METHODS Study Cohort and DataAs previously described [10], pregnant women in Kampala were enrolled, and oral swabs were collected in a standardized manner [11] from the mother and all children for quantitative polymerase chain reaction (qPCR) analysis of CMV [12]. Blood samples were collected from the infants at 6 weeks of age and every 4 months thereafter. Oral swabs and plasma samples were tested for CMV, using real-time qPCR. Primary infection was defined virologically and serologically as described elsewhere [10]. Additional information about subject selection is provided in the Supplementary Materials. This study was approved by all relevant institutional review boards in Uganda, the United States, and Canada. Written informed consent was obtained from all study participants or their guardians. Statistical Analysis and Classification of EpisodesEpisode duration was defined as the interval from the start of oral shedding until the end of observation. Correlations between same-day log 10 copies of CMV in plasma and oral swabs were calculated using Pearson correlation for all values and for positive values only. To see whether positive plasma samples were associated with higher oral log 10 CMV levels, we performed ...

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“…There is no vaccine for HCV and for more than a decade the standard-of-care of pegylated interferon-alpha (IFN) and ribavirin was suboptima [3]. However the recent advent of direct-acting antivirals (DAAs) allows for interferon-free, all-oral treatment yielding cure rates exceeding 90% with pangenotypic activity and shorter durations of therapy (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) weeks) compared to IFN-based therapy (24-48 weeks [4]). While these highly effective DAAs are considered one of the greatest achievements in medicine, significant challenges remain for eliminating HCV infection such as finding an optimal approach to current DAA failures, preventing re-infection, identifying all those infected and the high cost of the new DAAs which represents a major barrier to treating the populations that are most affected by HCV [3].…”

Section: Introductionmentioning

confidence: 99%

“…Mathematical models are valuable tools for understanding the in vivo serum dynamics of viruses that trigger both persistent infection (e.g., HIV-1 [6][7][8][9], hepatitis B virus [10][11][12], hepatitis D virus [13][14][15], Theiler murine encephalomyelitis virus [16], herpes simplex virus [17] and HCV [18][19][20]) and acute infection (e.g., influenza A [21][22][23] and ebola [24]). Mathematical modeling is also improving our understanding of intracellular viral genome dynamics [25][26][27][28] and the quantitative events that underlie the immune response to pathogens [6,9].…”

Section: Introductionmentioning

confidence: 99%

“…Mathematical modeling is also improving our understanding of intracellular viral genome dynamics [25][26][27][28] and the quantitative events that underlie the immune response to pathogens [6,9]. The standard model for HCV kinetics during treatment provided many insights into the effectiveness and mechanism of action of IFN and ribavirin (reviewed in [29,30]).…”

Section: Introductionmentioning

confidence: 99%

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A Robust and Efficient Numerical Method for RNA-Mediated Viral Dynamics

Reinharz

Churkin

Dahari

et al. 2017

Front. Appl. Math. Stat.

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The multiscale model of hepatitis C virus (HCV) dynamics, which includes intracellular viral RNA (vRNA) replication, has been formulated in recent years in order to provide a new conceptual framework for understanding the mechanism of action of a variety of agents for the treatment of HCV. We present a robust and efficient numerical method that belongs to the family of adaptive stepsize methods and is implicit, a Rosenbrock type method that is highly suited to solve this problem. We provide a Graphical User Interface that applies this method and is useful for simulating viral dynamics during treatment with anti-HCV agents that act against HCV on the molecular level.

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Mathematical modeling of viral kinetics under immune control during primary HIV-1 infection

Cited by 82 publications

References 37 publications

The Majority of CD4 ⁺ T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells

The Majority of CD4 ⁺ T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells

Dynamics of Persistent Oral Cytomegalovirus Shedding During Primary Infection in Ugandan Infants

A Robust and Efficient Numerical Method for RNA-Mediated Viral Dynamics

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Mathematical modeling of viral kinetics under immune control during primary HIV-1 infection

Cited by 82 publications

References 37 publications

The Majority of CD4 + T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells

The Majority of CD4 + T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells

Dynamics of Persistent Oral Cytomegalovirus Shedding During Primary Infection in Ugandan Infants

A Robust and Efficient Numerical Method for RNA-Mediated Viral Dynamics

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Product

Resources

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The Majority of CD4 ⁺ T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells

The Majority of CD4 ⁺ T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells