Post-exposure prophylaxis for SIV revisited: Animal model for HIV prevention

BACKGROUND: A 4-week, uninterrupted treatment with 9-(2-phosphonyl-methoxypropyly)adenine (PMPA, commonly called tenofovir) completely prevents simian immunodeficiency virus (SIV(mne)) infection in cynomolgus macaques if treatment begins within 24 hours after SIV(mne )inoculation, but is less effective if treatment is delayed or duration of treatment is shortened. Critical factors for efficacy include timing and duration of treatment, potency of antiretroviral drug and a contribution from antiviral immune responses. Therefore, we evaluated the impact of one or more treatment interruptions plus SIV(mne )re-exposures on efficacy of PMPA treatment to prevent SIV(mne )infection in cynomolgus macaques. We also evaluated whether macaques with pre-existing SIV immune responses show increased efficacy of treatment. Eight PMPA-treated, virus-negative and seronegative macaques, and five PMPA-treated, virus-negative but weakly or strongly seropositive macaques were re-inoculated with SIV(mne )and treated with PMPA starting 24 hr post inoculation. Thereafter, they received either a 5-week treatment involving one interruption plus one SIV(mne )challenge or a 10-week treatment involving six interruptions plus six SIV(mne )challenges early during treatment. Parameters measured were plasma SIV RNA, SIV-antibody response, CD4+ T lymphocyte subsets and in vivo CD8+ cell-suppression of virus infection. RESULTS: All seronegative macaques developed persistent antibody response beginning 4 to 8 weeks after stopping PMPA-treatment in absence of viremia in a majority of macaques and coinciding with onset of intermittent viremia in other macaques. In contrast, all weakly or strongly seropositive macaques showed immediate increase in titers (> 1600) of SIV antibodies, even before the end of PMPA-treatment, and in absence of detectable viremia. However, in vivo CD8+ -cell depletion revealed CD8 cell-suppression of viremia and persistence of virus in the macaques as long as 2 years after PMPA-treatment, even in aviremic macaques. Unlike untreated macaques, a treated macaque controlled viral replication and blocked CD4+ T cell depletion when challenged with a heterologus chimeric SIV/HIV-1 virus called SHIV(89.6P.) CONCLUSION: A single interruption plus one SIV(mne )challenge was as sufficient as six interruptions plus six SIV(mne )challenges in reducing efficacy of PMPA, but results in long-term persistence of virus infection suppressed by CD8+ cells. Efficacy of PMPA treatment was highest in macaques with pre-existing SIV immune responses

RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models

<p>Abstract</p> <p>Background</p> <p>Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important category of drugs for both chemotherapy and prevention of human immunodeficiency virus type 1 (HIV-1) infection. However, current non-human primate (NHP) models utilizing simian immunodeficiency virus (SIV) or commonly used chimeric SHIV (SIV expressing HIV-1 envelope) are inadequate due to the insensitivity to NNRTIs. To develop a NHP model for evaluation of NNRTI compounds, we characterized a RT-SHIV virus that was assembled by replacing the SIV_mac239reverse transcriptase (RT) with that of HIV-1HXB2. Since RT-SHIV exhibited <it>in vitro </it>characteristics of high infectivity, CCR5-usage, and sensitivity to HIV-1 specific NNRTIs, this virus was thought to be suitable for mucosal transmission and then was used to carry out a vaginal transmission study in pigtail macaques (<it>Macaca nemestrina</it>).</p> <p>Results</p> <p>RT-SHIV exhibited <it>in vitro </it>characteristics of an infectious CCR5-tropic chimeric virus. This virus was not only highly sensitive to HIV-1 RT specific NNRTIs; its replication was also inhibited by a variety of NRTIs and protease inhibitors. For <it>in vivo </it>vaginal transmission studies, macaques were either pretreated with a single dose of DMPA (depot medroxyprogesterone acetate) or left untreated before intravaginal inoculation with 500 or 1,000 TCID₅₀of RT-SHIV. All macaques became systemically infected by 2 or 3 weeks post-inoculation exhibiting persistent high viremia, marked CD4⁺T cell depletion, and antiviral antibody response. DMPA-pretreated macaques showed a higher mean plasma viral load after the acute infection stage, highly variable antiviral antibody response, and a higher incidence of AIDS-like disease as compared with macaques without DMPA pretreatment.</p> <p>Conclusion</p> <p>This chimeric RT-SHIV has exhibited productive replication in both macaque and human PBMCs, predominantly CCR5-coreceptor usage for viral entry, and sensitivity to NNRTIs as well as other anti-HIV compounds. This study demonstrates rapid systemic infection in macaques following intravaginal exposure to RT-SHIV. This RT-SHIV/macaque model could be useful for evaluation of NNRTI-based therapies, microbicides, or other preventive strategies.</p

Aircraft route recovery based on distributed integer programming method

In order to further promote the application and development of unmanned aviation in the manned field, and reduce the difficulty that airlines cannot avoid due to unexpected factors such as bad weather, aircraft failure, and so on, the problem of restoring aircraft routes has been studied. To reduce the economic losses caused by flight interruption, this paper divides the repair problem of aircraft operation plans into two sub problems, namely, the generation of flight routes and the reallocation of aircraft. Firstly, the existing fixed-point iteration method proposed by Dang is used to solve the feasible route generation model based on integer programming. To calculate quickly and efficiently, a segmentation method that divides the solution space into mutually independent segments is proposed as the premise of distributed computing. The feasible route is then allocated to the available aircraft to repair the flight plan. The experimental results of two examples of aircraft fault grounding and airport closure show that the method proposed in this paper is effective for aircraft route restoration

Acteoside From Ligustrum robustum (Roxb.) Blume Ameliorates Lipid Metabolism and Synthesis in a HepG2 Cell Model of Lipid Accumulation

We aimed to ascertain the mechanism underlying the effects of acteoside (ACT) from Ligustrum robustum (Roxb.) Blume (Oleaceae) on lipid metabolism and synthesis. ACT, a water-soluble phenylpropanoid glycoside, is the most abundant and major active component of L. robustum; the leaves of L. robustum, known as kudingcha (bitter tea), have long been used in China as an herbal tea for weight loss. Recently, based on previous studies, our team reached a preliminary conclusion that phenylpropanoid glycosides from L. robustum most likely contribute substantially to reducing lipid levels, but the mechanism remains unclear. Here, we conducted an in silico screen of currently known phenylethanoid glycosides from L. robustum and attempted to explore the hypolipidemic mechanism of ACT, the representative component of phenylethanoid glycosides in L. robustum, using RNA-seq technology, quantitative real-time PCR (qPCR) and Western blotting. First, the screening results for six compounds were docked with 15 human protein targets, and 3 of 15 protein targets were related to cardiovascular diseases. Based on previous experimental data and docking results, we selected ACT, which exerted positive effects, for further study. We generated a lipid accumulation model using HepG2 cells treated with a high concentration of oleic acid and then extracted RNA from cells treated for 24 h with 50 μmol/L ACT. Subsequently, we performed a transcriptomic analysis of the RNA-seq results, which revealed a large number of differentially expressed genes. Finally, we randomly selected some genes and proteins for further validation using qPCR and Western blotting; the results agreed with the RNA-seq data and confirmed their reliability. In conclusion, our experiments proved that ACT from L. robustum alters lipid metabolism and synthesis by regulating the expression of multiple genes, including Scarb1, Scarb2, Srebf1, Dhcr7, Acat2, Hmgcr, Fdft1, and Lss, which are involved several pathways, such as the glycolytic, AMPK, and fatty acid degradation pathways

A cold high-pressure system over North China hinders the southward migration of Mythimna separata in autumn

Background In warm regions or seasons of the year, the planetary boundary layer is occupied by a huge variety and quantity of insects, but the southward migration of insects (in East Asia) in autumn is still poorly understood. Methods We collated daily catches of the oriental armyworm (Mythimna separata) moth from 20 searchlight traps from 2014 to 2017 in China. In order to explore the autumn migratory connectivity of M. separata in East China, we analyzed the autumn climate and simulated the autumn migration process of moths. Results The results confirmed that northward moth migration in spring and summer under the East Asian monsoon system can bring rapid population growth. However, slow southerly wind (blowing towards the north) prevailed over the major summer breeding area in North China (33°–40° N) due to a cold high-pressure system located there, and this severely disrupts the autumn ‘return’ migration of this pest. Less than 8% of moths from the summer breeding area successfully migrated back to their winter-breeding region, resulting in a sharp decline of the population abundance in autumn. As northerly winds (blowing towards the south) predominate at the eastern periphery of a high-pressure system, the westward movement of the high-pressure system leads to more northerlies over North China, increasing the numbers of moths migrating southward successfully. Therefore, an outbreak year of M. separata larvae was associated with a more westward position of the high-pressure system during the previous autumn. Conclusion These results indicate that the southward migration in autumn is crucial for sustaining pest populations of M. separata, and the position of the cold high-pressure system in September is a key environmental driver of the population size in the next year. This study indicates that the autumn migration of insects in East China is more complex than previously recognized, and that the meteorological conditions in autumn are an important driver of migratory insects’ seasonal and interannual population dynamics