Prophylactic vaccination of rhesus macaques with rhesus cytomegalovirus (RhCMV) vectors expressing simian immunodeficiency virus (SIV) antigens (RhCMV/SIV) elicits immune responses that stringently ...control highly pathogenic SIV infection, with subsequent apparent clearance of the infection, in ~50% of vaccinees. In contrast, here, we show that therapeutic RhCMV/SIV vaccination of rhesus macaques previously infected with SIV and given continuous combination antiretroviral therapy (cART) beginning 4-9 d post-SIV infection does not mediate measurable SIV reservoir clearance during over 600 d of follow-up on cART relative to RhCMV/control vaccination. However, none of the six animals started on cART on day four or five, across both RhCMV/SIV- and RhCMV/control-vaccinated groups, those rhesus macaques with SIV reservoirs most closely resembling those of prophylactically RhCMV/SIV-vaccinated and protected animals early in their course, showed post-cART viral rebound with up to nine months of follow-up. Moreover, at necropsy, these rhesus macaques showed little to no evidence of replication-competent SIV. These results suggest that the early SIV reservoir is limited in durability and that effective blockade of viral replication and spread in this critical time window by either pharmacologic or immunologic suppression may result in reduction, and potentially loss, of rebound-competent virus over a period of ~two years.
A relatively new method has been developed to stop external corrosion and structurally reinforce steel pipes by external wrapping of damaged sections using fibre reinforced polymer (FRP) materials. ...Several different defect geometries representing corrosion patches on steel pipe were characterized using finite-element analysis, by changing the circumferential length of the defect. Pipe vessels containing these defects along with the composite structural repairs were modeled and the results were compared to field tests to determine the effectiveness of the repairs. It was found that the defect width around the circumference had little impact on the ultimate rupture pressure of the repaired vessel, but influenced the stress state in the underlying pipe substrate.
Dynamic traffic assignment (DTA) research has advanced greatly in terms of deployability, computational feasibility, and representing complex temporal phenomena. There have also been substantial ...contributions regarding various aspects of stochasticity within DTA. However, there are persisting limitations in terms of approaches which are both computationally tractable and provide more detailed representation of stochastic aspects. This paper explores the application of a novel Strategic User Equilibrium DTA (StrDTA) modelling framework, which captures the impact of users making a priori route choice decisions based on the knowledge of a range of possible travel demand scenarios (e.g. differing days or representative situations). The resulting stochastic DTA problem becomes complex due to the integration of multiple demand scenarios and the algorithmic adjustments necessary to find optimal paths. A new solution framework is proposed which still permits implementation, and a detailed case study is presented for the Sydney Central Business District network. Results demonstrate the importance of accounting for stochasticity in the routing algorithm rather than relying on assumptions of average values.
Flumethrin is one of many pesticides used for the control and treatment of varroatosis in honey bees and for the control of mosquitoes and ticks in the environment. For the control of varroatosis, ...flumethrin is applied to hives formulated as a plastic strip for several weeks. During this time, honey bees are treated topically with flumethrin, and hive products may accumulate the pesticide. Honey bees may indirectly ingest flumethrin through hygienic behaviors during the application period and receive low doses of flumethrin through comb wax remodeling after the application period. The goal of our study was to determine the acute oral toxicity of flumethrin and observe the acute effects on motor coordination in honey bees (Apis mellifera anatoliaca). Six doses (between 0.125 and 4.000 µg per bee) in a geometric series were studied. The acute oral LD50 of flumethrin was determined to be 0.527 and 0.178 µg per bee (n = 210, 95% CI) for 24 and 48 h, respectively. Orally administered flumethrin is highly toxic to honey bees. Oral flumethrin disrupted the motor coordination of honey bees. Honey bees that ingested flumethrin exhibited convulsions in the antennae, legs, and wings at low doses. At higher doses, partial and total paralysis in the antennae, legs, wings, proboscises, bodies, and twitches in the antennae and legs were observed.
Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently HIV-infected CD4+ T cells. We engineered an anti-PD-1 chimeric ...antigen receptor (CAR) to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in SIVmac239-infected rhesus macaques (RMs). Adoptive transfer of anti-PD-1 CAR T cells was done in 2 SIV-naive and 4 SIV-infected RMs on antiretroviral therapy (ART). In 3 of 6 RMs, anti-PD-1 CAR T cells expanded and persisted for up to 100 days concomitant with the depletion of PD-1+ memory T cells in blood and tissues, including lymph node CD4+ follicular helper T (TFH) cells. Loss of TFH cells was associated with depletion of detectable SIV RNA from the germinal center (GC). However, following CAR T infusion and ART interruption, there was a marked increase in SIV replication in extrafollicular portions of lymph nodes, a 2-log higher plasma viremia relative to controls, and accelerated disease progression associated with the depletion of CD8+ memory T cells. These data indicate anti-PD-1 CAR T cells depleted PD-1+ T cells, including GC TFH cells, and eradicated SIV from this immunological sanctuary.
IL-15 has been implicated as a key regulator of T and NK cell homeostasis in multiple systems; however, its specific role in maintaining peripheral T and NK cell populations relative to other γ-chain ...(γc) cytokines has not been fully defined in primates. In this article, we address this question by determining the effect of IL-15 inhibition with a rhesusized anti-IL-15 mAb on T and NK cell dynamics in rhesus macaques. Strikingly, anti-IL-15 treatment resulted in rapid depletion of NK cells and both CD4(+) and CD8(+) effector memory T cells (TEM) in blood and tissues, with little to no effect on naive or central memory T cells. Importantly, whereas depletion of NK cells was nearly complete and maintained as long as anti-IL-15 treatment was given, TEM depletion was countered by the onset of massive TEM proliferation, which almost completely restored circulating TEM numbers. Tissue TEM, however, remained significantly reduced, and most TEM maintained very high turnover throughout anti-IL-15 treatment. In the presence of IL-15 inhibition, TEM became increasingly more sensitive to IL-7 stimulation in vivo, and transcriptional analysis of TEM in IL-15-inhibited monkeys revealed engagement of the JAK/STAT signaling pathway, suggesting alternative γc cytokine signaling may support TEM homeostasis in the absence of IL-15. Thus, IL-15 plays a major role in peripheral maintenance of NK cells and TEM However, whereas most NK cell populations collapse in the absence of IL-15, TEM can be maintained in the face of IL-15 inhibition by the activity of other homeostatic regulators, most likely IL-7.
Although IL-15 has been implicated in the pathogenic hyperimmune activation that drives progressive HIV and SIV infection, as well as in the generation of HIV/SIV target cells, it also supports NK ...and T cell homeostasis and effector activity, potentially benefiting the host. To understand the role of IL-15 in SIV infection and pathogenesis, we treated two cohorts of SIVmac239-infected rhesus macaques (RM;
), one with chronic infection, the other with primary infection, with a rhesusized, IL-15-neutralizing mAb (versus an IgG isotype control) for up to 10 wk (
= 7-9 RM per group). In both cohorts, anti-IL-15 was highly efficient at blocking IL-15 signaling in vivo, causing 1) profound depletion of NK cells in blood and tissues throughout the treatment period; 2) substantial, albeit transient, depletion of CD8
effector memory T cells (T
) (but not the naive and central memory subsets); and 3) CD4
and CD8
T
hyperproliferation. In primary infection, reduced frequencies of SIV-specific effector T cells in an extralymphoid tissue site were also observed. Despite these effects, the kinetics and extent of SIV replication, CD4
T cell depletion, and the onset of AIDS were comparable between anti-IL-15- and control-treated groups in both cohorts. However, RM treated with anti-IL-15 during primary infection manifested accelerated reactivation of RM rhadinovirus. Thus, IL-15 support of NK cell and T
homeostasis does not play a demonstrable, nonredundant role in SIV replication or CD4
T cell deletion dynamics but may contribute to immune control of oncogenic γ-herpesviruses.
Aging is associated with gradual deterioration of adaptive immune function, a hallmark of which is the profound loss of naive T cells (TN) associated with decline in thymic output and export of new ...cells into the peripheral T cell pool. Because the lymphotropic cytokine IL-7 plays crucial roles in both development of TN in the thymus and TN homeostasis in the periphery, we sought to determine the extent to which therapeutic administration of IL-7 could reverse TN deficiency in aging rhesus macaques (RM), either by enhancement of the demonstrably reduced thymopoiesis or by peripheral TN expansion. Our results indicate that treatment of both adult (8-15 y) and old (>20 y) RM with recombinant simian IL-7 (rsIL-7) results in only transient increases in peripheral CD4(+) and CD8(+) TN numbers with no long-term benefit, even with repeated therapy. This transient effect was due to peripheral TN expansion and not enhanced thymic function, and appeared to be limited by induction of IL-7 nonresponsiveness. However, rsIL-7 therapy had a more promising effect on the central memory T cell (TCM) population (both CD4(+) and CD8(+)) in adult and old RM, doubling the numbers of these cells in circulation and maintaining this larger population long term. IL-7 therapy did not reduce TCR diversity of the memory T cell compartment, suggesting that rsIL-7-induced expansion was symmetrical. Thus, although rsIL-7 failed to counter age-associated TN loss, the ability of this therapy to expand clonotypically diverse CD4(+) and CD8(+) TCM populations might potentially improve adaptive immune responsiveness in the elderly.
Suicidal defense is an important and effective attribute of some highly social animals. It has been suggested that the defensive behavior of biting onto raiders is suicidal in stingless bees; ...however, the mechanisms causing death are unclear. We conducted the first test of the effect of agonistic encounters on death and injury rates of guards of a stingless bee,
Tetragonisca angustula
, that bit both conspecific and heterospecific invaders within plastic tubes
. Tetragonisca angustula
guards bit and immobilized invading bees for long durations and had the ability to release their hold, but rarely did so unless the other bee died. In our assays, which lasted hours to up to 1 day, the probability of death during nest defense by
T. angustula
was 5–7%. Bitten invading bees fought back, often causing injury and sometimes death of the biting
T. angustula
.
Tetragonisca angustula
foragers can survive for 7 days without food and so death by starvation of guards during day-long encounters seems unlikely. Death rates of biting guards holding non-nestmates on the ground may be higher in the field due to susceptibility to predation. Defensive biting of stingless bees effectively protects the nest, and most guards likely are able to return to their tasks after a raid is thwarted, though studies in a more naturalistic setting are needed.
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