Rapid Clearance of Simian Immunodeficiency Virus Particles from Plasma of Rhesus Macaques

Zhang, Linqi; Dailey, Peter J.; Tian, He; Gettie, Agegnehu; Bonhoeffer, Sebastian; Perelson, Alan S.; Ho, David D.

doi:10.1128/jvi.73.1.855-860.1999

Cited by 83 publications

(24 citation statements)

References 24 publications

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“…Higher estimates are obtained because cell death and viral clearance are o¡set by release of virus from FDCs. Recent direct measurements of viral clearance (Zhang et al 1999a;Ramratnam et al 1999;Igarashi et al 1999) are consistent with higher estimates of c.…”

Section: (B) Estimates Of¯and C When Fdcs Are Consideredmentioning

confidence: 53%

Influence of follicular dendritic cells on HIV dynamics

Hlavacek

Stilianakis

Perelson

2000

Phil. Trans. R. Soc. Lond. B

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In patients infected with human immunodeficiency virus type 1 (HIV-1), a large amount of virus is associated with follicular dendritic cells (FDCs) in lymphoid tissue. To assess the influence of FDCs on viral dynamics during antiretroviral therapy we have developed a mathematical model for treatment of HIV-1 infection that includes FDCs. Here, we use this model to analyse measurements of HIV-1 dynamics in the blood and lymphoid tissue of a representative patient, who was treated with a combination of HIV-1 reverse transcriptase and protease inhibitors. We show that loss of virus from FDCs during therapy can make a much larger contribution to plasma virus than production of virus by infected cells. This result challenges the notion that long-lived infected cells are a significant source of HIV-1 during drug therapy. Due to release of FDC-associated virus, we find that it is necessary to revise upward previous estimates of c, the rate at which free virus is cleared, and delta, the rate at which productively infected cells die. Furthermore, we find that potentially infectious virus, present before treatment, is released from FDCs during therapy and that the persistence of this virus can be affected by whether therapy includes reverse transcriptase inhibitors.

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Section: (B) Estimates Of¯and C When Fdcs Are Consideredmentioning

confidence: 53%

Influence of follicular dendritic cells on HIV dynamics

Hlavacek

Stilianakis

Perelson

2000

Phil. Trans. R. Soc. Lond. B

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“…It is also possible that mutations that lead to escape from the CTL response also affect viral infectivity, β, especially if they occur in the envelope, reverse transcriptase or integrase-coding regions of the viral genome. Because viral particles are short-lived in vivo [41,44,53], a quasi-steady state is rapidly established in which the density of viral particles is proportional to the density of virus-infected cells,…”

Section: Mathematical Modelmentioning

confidence: 99%

Mathematical modeling of escape of HIV from cytotoxic T lymphocyte responses

2013

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Human immunodeficiency virus (HIV-1 or simply HIV) induces a persistent infection, which in the absence of treatment leads to AIDS and death in almost all infected individuals. HIV infection elicits a vigorous immune response starting about 2–3 weeks post infection that can lower the amount of virus in the body, but which cannot eradicate the virus. How HIV establishes a chronic infection in the face of a strong immune response remains poorly understood. It has been shown that HIV is able to rapidly change its proteins via mutation to evade recognition by virus-specific cytotoxic T lymphocytes (CTLs). Typically, an HIV-infected patient will generate 4–12 CTL responses specific for parts of viral proteins called epitopes. Such CTL responses lead to strong selective pressure to change the viral sequences encoding these epitopes so as to avoid CTL recognition. Indeed, the viral population “escapes” from about half of the CTL responses by mutation in the first year. Here we review experimental data on HIV evolution in response to CTL pressure, mathematical models developed to explain this evolution, and highlight problems associated with the data and previous modeling efforts. We show that estimates of the strength of the epitope-specific CTL response depend on the method used to fit models to experimental data and on the assumptions made regarding how mutants are generated during infection. We illustrate that allowing CTL responses to decay over time may improve the fit to experimental data and provides higher estimates of the killing efficacy of HIV-specific CTLs. We also propose a novel method for simultaneously estimating the killing efficacy of multiple CTL populations specific for different epitopes of HIV using stochastic simulations. Lastly, we show that current estimates of the efficacy at which HIV-specific CTLs clear virus-infected cells can be improved by more frequent sampling of viral sequences and by combining data on sequence evolution with experimentally measured CTL dynamics.

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“…We constructed the following equations to describe the viral dynamics depicted schematically in Figure 1. (12,42,43) in the absence of administered bNAbs with the rate constant c. Administered bNAbs enhance the viral clearance rate by a time-dependent amount, A k AV , proportional to the instantaneous serum concentration of the bNAbs, A, with the proportionality constant A k . APCs are assumed not to be limiting and take up SHIV-specific antigen from I for presentation with the first-order rate constant  .…”

Section: Mathematical Modelmentioning

confidence: 99%

Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection

Desikan

Raja

Dixit

2019

Preprint

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Title: 129 characters | Abstract: 250 words | Importance: 120 words | Text: ~48000 characters 24 including figure captions and references | Figures: 6 | References: 58 25 Supplementary text: 1 | Supplementary figures: 11 | Supplementary tables: 10 | Supplementary 26 database: 1 27 42 viremic control. Early bNAb therapy lowered viremia, which also limited CTL exhaustion, and 43 improved CTL stimulation via cross-presentation. Post bNAb therapy, viremia resurged but in 44 the presence of a primed CTL population, which eventually controlled the infection. 45 Antiretroviral therapy suppresses viremia but does not enhance CTL stimulation, which limits 46 its ability to elicit post-treatment control. Our model suggests bNAb-based intervention 47 Importance 49 Antiretroviral therapy (ART) for HIV-1 infection is life-long. Remarkably, a recent study 50 showed that 3 weekly doses of HIV-1 broadly neutralizing antibodies (bNAbs) soon after 51 infection kept viral levels controlled for years in macaques. If translated to humans, this bNAb 52 therapy may elicit a functional cure of HIV-1 infection, eliminating the need for life-long 53 treatment. How early bNAb therapy works in macaques remains unknown. Here, we elucidate 54 the mechanism using mathematical modeling and analysis of in vivo data. Early bNAb therapy 55 suppresses viremia, reduces cytotoxic T lymphocyte (CTL) exhaustion, and enhances antigen 56 uptake and CTL stimulation, which collectively drive infection to lasting control. Model 57 predictions fit the complex in vivo data quantitatively and suggest new avenues to optimize 58 bNAb-based interventions. 59 60 Current antiretroviral therapies (ART) for HIV-1 infection control viremia in infected 61 individuals but are unable to eradicate the virus (1). A reservoir of latently infected cells, which 62 is established soon after infection (2), escapes drugs and the host immune response (3), is long-63 lived (4, 5), and can reignite infection following the cessation of therapy (6), presents the key 64 obstacle to sterilizing cure. Efforts are now aimed at eliciting a "functional cure" of the 65 infection, where the virus can be controlled without life-long treatment even though eradication 66 is not possible (7). That functional cure can be achieved has been demonstrated by the 67 VISCONTI trial, where a subset of patients, following early initiation of ART, maintained 68 undetectable viremia long after the cessation of treatment (8). A limitation, however, is that the 69 subset that achieves post-treatment control with ART is small, 5-15% of the patients treated 70 (9). In a major advance, Nishimura et al. (10) found recently that early, short-term passive 71 immunization with a combination of two HIV-1 broadly neutralizing antibodies (bNAbs) 72 elicited lasting control of viremia in 10 of 13, or nearly 77%, of SHIV-infected macaques 73 treated. This high success rate raises the prospect of achieving functional cure in all HIV-1 74 infected individuals using short-term bNAb therapy. Efforts have been initiated to d...

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Rapid Clearance of Simian Immunodeficiency Virus Particles from Plasma of Rhesus Macaques

Cited by 83 publications

References 24 publications

Influence of follicular dendritic cells on HIV dynamics

Influence of follicular dendritic cells on HIV dynamics

Mathematical modeling of escape of HIV from cytotoxic T lymphocyte responses

Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection

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