scholarly journals Dynamics of latent HIV under clonal expansion

2021 ◽  
Vol 17 (12) ◽  
pp. e1010165
Author(s):  
John M. Murray
Keyword(s):  
Half Life ◽  
Maximum Size ◽  
Decay Rates ◽  
Latent Reservoir ◽  
Homeostatic Proliferation ◽  
Art Initiation ◽  
Slow Decay ◽  
Latent Hiv ◽  
The Individual ◽  
Integration Data

The HIV latent reservoir exhibits slow decay on antiretroviral therapy (ART), impacted by homeostatic proliferation and activation. How these processes contribute to the total dynamic while also producing the observed profile of sampled latent clone sizes is unclear. An agent-based model was developed that tracks individual latent clones, incorporating homeostatic proliferation of cells and activation of clones. The model was calibrated to produce observed latent reservoir dynamics as well as observed clonal size profiles. Simulations were compared to previously published latent HIV integration data from 5 adults and 3 children. The model simulations reproduced reservoir dynamics as well as generating residual plasma viremia levels (pVL) consistent with observations on ART. Over 382 Latin Hypercube Sample simulations, the median latent reservoir grew by only 0.3 log10 over the 10 years prior to ART initiation, after which time it decreased with a half-life of 15 years, despite number of clones decreasing at a faster rate. Activation produced a maximum size of genetically intact clones of around one million cells. The individual simulation that best reproduced the sampled clone profile, produced a reservoir that decayed with a 13.9 year half-life and where pVL, produced mainly from proliferation, decayed with a half-life of 10.8 years. These slow decay rates were achieved with mean cell life-spans of only 14.2 months, due to expansion of the reservoir through proliferation and activation. Although the reservoir decayed on ART, a number of clones increased in size more than 4,000-fold. While small sampled clones may have expanded through proliferation, the large sizes exclusively arose from activation. Simulations where homeostatic proliferation contributed more to pVL than activation, produced pVL that was less variable over time and exhibited fewer viral blips. While homeostatic proliferation adds to the latent reservoir, activation can both add and remove latent cells. Latent activation can produce large clones, where these may have been seeded much earlier than when first sampled. Elimination of the reservoir is complicated by expanding clones whose dynamic differ considerably to that of the entire reservoir.

scholarly journals The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation

2019 ◽  
Vol 11 (513) ◽  
pp. eaaw5589 ◽  
Author(s):  
Melissa-Rose Abrahams ◽  
Sarah B. Joseph ◽  
Nigel Garrett ◽  
Lynn Tyers ◽  
Matthew Moeser ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Infection ◽  
Latent Reservoir ◽  
Viral Reservoirs ◽  
Art Initiation ◽  
Therapy Initiation ◽  
Hiv Positive Women ◽  
Latent Hiv ◽  
Viral Sequences ◽  
Hiv 1

Although antiretroviral therapy (ART) is highly effective at suppressing HIV-1 replication, the virus persists as a latent reservoir in resting CD4+ T cells during therapy. This reservoir forms even when ART is initiated early after infection, but the dynamics of its formation are largely unknown. The viral reservoirs of individuals who initiate ART during chronic infection are generally larger and genetically more diverse than those of individuals who initiate therapy during acute infection, consistent with the hypothesis that the reservoir is formed continuously throughout untreated infection. To determine when viruses enter the latent reservoir, we compared sequences of replication-competent viruses from resting peripheral CD4+ T cells from nine HIV-positive women on therapy to viral sequences circulating in blood collected longitudinally before therapy. We found that, on average, 71% of the unique viruses induced from the post-therapy latent reservoir were most genetically similar to viruses replicating just before ART initiation. This proportion is far greater than would be expected if the reservoir formed continuously and was always long lived. We conclude that ART alters the host environment in a way that allows the formation or stabilization of most of the long-lived latent HIV-1 reservoir, which points to new strategies targeted at limiting the formation of the reservoir around the time of therapy initiation.

Analysis of Spin Polarisation Transients in Periodically Photo-excited Triplet States

1975 ◽  
Vol 30 (5) ◽  
pp. 571-582 ◽  
Author(s):  
C. J. Winscom
Keyword(s):  
Lattice Relaxation ◽  
Rectangular Pulse ◽  
Decay Rates ◽  
Spin Lattice Relaxation ◽  
Pulse Excitation ◽  
Triplet States ◽  
Relaxation Rates ◽  
Spin Sublevel ◽  
Spin Lattice ◽  
The Individual

Abstract The behaviour of spin sublevel populations with time following periodic photo-excitation is ex-amined. The treatment is limited to conditions of magnetic field strength and temperature for which the spin lattice relaxation rates dominate the individual spin sublevel decay rates. The response of the system to three modes of excitation is considered: (i) continuous excitation using a time-independent intensity (ii) periodic rectangular pulse excitation and (iii) periodic waveform excitation. A convenient correspondence between the various forms of solutions is pointed out. The requirements of an experiment to determine spin-lattice relaxation rates in organic triplets at 77 K are discussed.

Pharmacokinetics and Tissue Residues of Sulfathiazole and Sulfamethazine in Pigs

1994 ◽  
Vol 57 (9) ◽  
pp. 796-801 ◽  
Author(s):  
LIEVE S. G. VAN POUCKE ◽  
CARLOS H. VAN PETEGHEM
Keyword(s):  
Intravenous Injection ◽  
Half Life ◽  
Intramuscular Injection ◽  
Compartment Model ◽  
Absolute Bioavailability ◽  
Pharmacokinetic Parameters ◽  
Tissue Concentrations ◽  
Single Intravenous Injection ◽  
The Individual ◽  
Residue Study

The plasma pharmacokinetics and tissue penetration of sulfathiazole (ST) and sulfamethazine (SM) after intravenous and intramuscular injection in pigs were studied. Following a single intravenous dose of 40 mg ST/kg of bodyweight or 80 mg SM/kg of bodyweight, the plasma ST and SM concentrations were best fitted to a two-compartment model. The areas under the curve were 447 ± 39 and 1485 ± 41 mg/h/L, clearances were 0.090 ± 0.007 and 0.054 ± 0.001 L/kg/h, volumes of distribution were 1.16 ± 0.16 and 0.77 ± 0.06 L/kg, half-lifes in distribution phase were l.18 ± 0.57 and 0.23 ± 0.16 h and half-lifes in eliminations phase were 9.0 ± l.6 and 9.8 ± 0.6 h. When the two compounds were administered simultaneously as a single intravenous injection, the pharmacokinetic parameters for ST were not significantly different. The values for SM show statistical differences for some important parameters: α, β and the AUC0–>∞ were significantly decreased and t1/2α, Vd and CIB were significantly increased. It can be concluded that after a single intravenous injection of 40 mg/kg, sulfathiazole has a high tl/2β resulting in higher tissue concentrations. This half-life, which is higher than what is reported in the literature, is not influenced by the simultaneous presence of sulfamethazine. The tl/2β for sulfamethazine after a single intravenous injection of 80 mg/kg is comparable to the data from the literature and is not influenced by the presence of sulfathiazole. Sulfathiazole and SM were also administered simultaneously as an intramuscular injection to healthy pigs at a dosage of 40 and 80 mg/kg bodyweight. Pharmacokinetic experiments were conducted on three pigs. From this pharmacokinetic study it can be concluded that upon a single intramuscular administration of 40 mg/kg of ST and 80 mg/kg of SM the absolute bioavailability in pigs is 0.92 ± 0.04 for ST and l.01 ± 0.07 for SM. Six pigs received five intramuscular im) injections as a single dose of ST and SM every 24 h for five consecutive days for the residue study. The pigs were slaughtered at different times after the last dose was given and samples were taken from various tissues and organs. Concentrations were determined by a microbiological method and a HPTLC method. No edible tissue contained more than 100 μg/kg of the individual sulfonamides after 10 days of withdrawal. It means that adult animals which have a shorter half-life and thus lower tissue concentrations will certainly meet the economic community EC) maximum residue limits after a 10 days withdrawal period.

Direct photoionization measurements of slow decay rates of vibrationally overexcited (CF3)3CI molecules in the ground electronic state in a beam

1986 ◽  
Vol 127 (5) ◽  
pp. 438-444 ◽  
Author(s):  
V.M. Apatin ◽  
V.S. Letokhov ◽  
V.N. Lokhman ◽  
G.N. Makarov ◽  
V.N. Bagratashvili ◽  
...  
Keyword(s):  
Electronic State ◽  
Decay Rates ◽  
Ground Electronic State ◽  
Slow Decay

Beta-decay half-lives of the extremely neutron-rich nuclei in the closed-shell N = 50, 82, 126 groups

2021 ◽  
Author(s):  
Nguyen Kim Uyen ◽  
Kyung Yuk Chae ◽  
NgocDuy Nguyen ◽  
DuyLy Nguyen
Keyword(s):  
Half Life ◽  
Random Phase ◽  
Closed Shell ◽  
Decay Rates ◽  
Magic Numbers ◽  
Β Decay ◽  
R Process ◽  
Neutron Rich Isotopes ◽  
Semi Empirical ◽  
The Impact

Abstract The β--decay half-lives of extremely neutron-rich nuclei are important for understanding nucleosynthesis in the r-process. However, most of their half-lives are unknown or very uncertain, leading to the need for reliable calculations. In this study, we updated the coefficients in recent semi-empirical formulae using the newly updated mass (AME2020) and half-life (NUBASE2020) databases to improve the accuracy of the half-life prediction. In particular, we developed a new empirical model for better calculations of the β--decay half-lives of isotopes ranging in Z = 10 – 80 and N = 15-130. We examined the β--decay half-lives of the extremely neutron-rich isotopes at and around the neutron magic numbers of N = 50, 82, and 126 using either five different semi-empirical models or finite-range droplet model and quasi-particle random phase approximation (FRDM+QRPA) method. The β--decay rates derived from the estimated half-lives were used in calculations to evaluate the impact of the half-life uncertainties of the investigated nuclei on the abundance of the r-process. The results show that the half-lives mostly range in 0.001 < T1/2 < 100 s for the nuclei with a ratio of N/Z < 1.9; however, they differ significantly for those with the ratio of N/Z > 1.9. The half-life differences among the models were found to range from a few factors (for N/Z < 1.9 nuclei) to four orders of magnitude (for N/Z > 1.9). These discrepancies lead to a large uncertainty, which is up to four orders of magnitude, in the r-process abundance of isotopes. We also found that the multiple-reflection time-of-flight (MR-TOF) technique is preferable for precise mass measurements because its measuring timescale applies to the half-lives of the investigated nuclei. Finally, the results of this study are useful for studies on the β-decay of unstable isotopes and astrophysical simulations.

Individual Growth and Reproduction

2019 ◽  
pp. 38-56
Author(s):  
Ken H. Andersen
Keyword(s):  
Life History ◽  
Growth Model ◽  
Life Histories ◽  
Maximum Size ◽  
Individual Growth ◽  
Energy Budgets ◽  
Asymptotic Size ◽  
The Individual ◽  
Growth And Reproduction

This chapter develops descriptions of how individuals grow and reproduce. More specifically, the chapter seeks to determine the growth and reproduction rates from the consumption rate, by developing an energy budget of the individual as a function of size. To that end, the chapter addresses the question of how an individual makes use of the energy acquired from consumption. It sets up the energy budgets of individuals by formulating the growth model using so-called life-history invariants, which are parameters that do not vary systematically between species. While the formulation of the growth model in terms of life-history invariants is largely successful, there is in particular one parameter that is not invariant between life histories: the asymptotic size (maximum size) of individuals in the population. This parameter plays the role of a master trait that characterizes most of the variation between life histories.

scholarly journals Selective Decay of Intact HIV-1 Proviral DNA on Antiretroviral Therapy

2020 ◽  
Author(s):  
Rajesh T Gandhi ◽  
Joshua C Cyktor ◽  
Ronald J Bosch ◽  
Hanna Mar ◽  
Gregory M Laird ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Half Life ◽  
Plasma Viremia ◽  
Art Initiation ◽  
Markers Of Inflammation ◽  
Infected Cells ◽  
Selective Decay ◽  
Hiv 1 ◽  
Over Time ◽  
Residual Plasma Viremia

Abstract Background HIV-1 proviruses persist in people on antiretroviral therapy (ART) but most are defective and do not constitute a replication-competent reservoir. The decay of infected cells carrying intact compared with defective HIV-1 proviruses has not been well defined in people on ART. Methods We separately quantified intact and defective proviruses, residual plasma viremia, and markers of inflammation and activation in people on long-term ART. Results Among 40 participants tested longitudinally from a median of 7.1 years to 12 years after ART initiation, intact provirus levels declined significantly over time (median half-life, 7.1 years; 95% confidence interval [CI], 3.9–18), whereas defective provirus levels did not decrease. The median half-life of total HIV-1 DNA was 41.6 years (95% CI, 13.6–75). The proportion of all proviruses that were intact diminished over time on ART, from about 10% at the first on-ART time point to about 5% at the last. Intact provirus levels on ART correlated with total HIV-1 DNA and residual plasma viremia, but there was no evidence for associations between intact provirus levels and inflammation or immune activation. Conclusions Cells containing intact, replication-competent proviruses are selectively lost during suppressive ART. Defining the mechanisms involved should inform strategies to accelerate HIV-1 reservoir depletion.

scholarly journals Levers to Improve Antibiotic Treatment of Lambs via Drinking Water in Sheep Fattening Houses: The Example of the Sulfadimethoxine/Trimethoprim Combination

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 561
Author(s):  
Aude A. Ferran ◽  
Marlène Z. Lacroix ◽  
Alain Bousquet-Mélou ◽  
Ivain Duhil ◽  
Béatrice B. Roques
Keyword(s):  
Drinking Water ◽  
Oral Bioavailability ◽  
Half Life ◽  
Plasma Concentrations ◽  
Oral Route ◽  
Disease Spread ◽  
Bacterial Diseases ◽  
Terminal Half Life ◽  
High Interindividual Variability ◽  
The Individual

To limit the spread of bacterial diseases in sheep fattening houses, antibiotics are often administered collectively. Collective treatments can be delivered by drinking water but data on the drug’s solubility in water or on plasma exposure of the animals are lacking. We first assessed the solubility of products containing sulfadimethoxine (SDM), associated or not with trimethoprim (TMP), in different waters. We then compared in lambs the SDM and TMP pharmacokinetic profiles after individual intravenous (IV) and oral administrations of SDM-TMP in experimental settings (n = 8) and after a collective treatment by drinking water with SDM-TMP or SDM alone in a sheep fattening house (n = 100 for each treatment). The individual water consumption during the collective treatments was also monitored to characterize the ingestion variability. We showed that TMP had a short terminal half-life and very low oral bioavailability, demonstrating that it would be unable to potentiate SDM by oral route. Conversely, SDM had a long terminal half-life of 18 h and excellent oral bioavailability. However, delivery by drinking water resulted in a very high interindividual variability of SDM plasma concentrations, meaning that although disease spread could be controlled at the group level, some individuals would inevitably be under- or over-exposed to the antibiotic.

scholarly journals Characterization of Intact Proviruses in Blood and Lymph Node from HIV-Infected Individuals Undergoing Analytical Treatment Interruption

2019 ◽  
Vol 93 (8) ◽  
Author(s):  
Line K. Vibholm ◽  
Julio C. C. Lorenzi ◽  
Joy A. Pai ◽  
Yehuda Z. Cohen ◽  
Thiago Y. Oliveira ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Treatment Interruption ◽  
Latent Reservoir ◽  
Lymphoid Tissues ◽  
Viral Rebound ◽  
Analytical Treatment ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACT The role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy (ART) is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near-full-length (NFL) proviral DNA and env from viral outgrowth assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical treatment interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia. IMPORTANCE HIV-1 persists as a latent infection in CD4+ T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4+ T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination.

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