Efficient treatment and pre-exposure prophylaxis in rhesus macaques by an HIV fusion-inhibitory lipopeptide.

Two HIV fusion-inhibitory lipopeptides (LP-97 and LP-98) were designed with highly potent, long-acting antiviral activity. Monotherapy using a low dose of LP-98 sharply reduced viral loads and maintained long-term viral suppression in 21 SHIVSF162P3-infected rhesus macaques. We found that five treated monkeys achieved potential posttreatment control (PTC) efficacy and had lower viral DNA in deep lymph nodes, whereas monkeys with a stable viral rebound had higher viral DNA in superficial lymph nodes. The tissues of PTC monkeys exhibited significantly decreased quantitative viral outgrowth and fewer PD-1+ central memory CD4+ T cells, and CD8+ T cells contributed to virologic control efficacy. Moreover, LP-98 administrated as a pre-exposure prophylaxis (PrEP) provided complete protection against SHIVSF162P3 and SIVmac239 infections in 51 monkeys via intrarectal, intravaginal, or intravenous challenge. In conclusion, our lipopeptides exhibit high potential as an efficient HIV treatment or prevention strategy.

Single-dose rAAV5-based vaccine provides long-term protective immunity against SARS-CoV-2 and its variants.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus and its variants, has posed unprecedented challenges worldwide. Existing vaccines have limited effectiveness against SARS-CoV-2 variants. Therefore, novel vaccines to match mutated viral lineages by providing long-term protective immunity are urgently needed. We designed a recombinant adeno-associated virus 5 (rAAV5)-based vaccine (rAAV-COVID-19) by using the SARS-CoV-2 spike protein receptor binding domain (RBD-plus) sequence with both single-stranded (ssAAV5) and self-complementary (scAAV5) delivery vectors and found that it provides excellent protection from SARS-CoV-2 infection. A single-dose vaccination in mice induced a robust immune response; induced neutralizing antibody (NA) titers were maintained at a peak level of over 1:1024 more than a year post-injection and were accompanied by functional T-cell responses. Importantly, both ssAAV- and scAAV-based RBD-plus vaccines produced high levels of serum NAs against the circulating SARS-CoV-2 variants, including Alpha, Beta, Gamma and Delta. A SARS-CoV-2 virus challenge showed that the ssAAV5-RBD-plus vaccine protected both young and old mice from SARS-CoV-2 infection in the upper and lower respiratory tracts. Whole genome sequencing demonstrated that AAV vector DNA sequences were not found in the genomes of vaccinated mice one year after vaccination, demonstrating vaccine safety. These results suggest that the rAAV5-based vaccine is safe and effective against SARS-CoV-2 and several variants as it provides long-term protective immunity. This novel vaccine has a significant potential for development into a human prophylactic vaccination to help end the global pandemic.

Susceptibility and Attenuated Transmissibility of SARS-CoV-2 in Domestic Cats.

Domestic cats, an important companion animal, can be infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This has aroused concern regarding the ability of domestic cats to spread the virus that causes coronavirus disease 2019. We systematically demonstrated the pathogenesis and transmissibility of SARS-CoV-2 in cats. Serial passaging of the virus between cats dramatically attenuated the viral transmissibility, likely owing to variations of the amino acids in the receptor-binding domain sites of angiotensin-converting enzyme 2 between humans and cats. These findings provide insight into the transmissibility of SARS-CoV-2 in cats and information for protecting the health of humans and cats.

Sec-Eliminating the SARS-CoV-2 by AlGaN Based High Power Deep Ultraviolet Light Source.

The world-wide spreading of coronavirus disease (COVID-19) has greatly shaken human society, thus effective and fast-speed methods of non-daily-life-disturbance sterilization have become extremely significant. In this work, by fully benefitting from high-quality AlN template (with threading dislocation density as low as ≈6×108 cm-2) as well as outstanding deep ultraviolet (UVC-less than 280 nm) light-emitting diodes (LEDs) structure design and epitaxy optimization, high power UVC LEDs and ultra-high-power sterilization irradiation source are achieved. Moreover, for the first time, a result in which a fast and complete elimination of SARS-CoV-2 (the virus causes COVID-19) within only 1 s is achieved by the nearly whole industry-chain-covered product. These results advance the promising potential in UVC-LED disinfection particularly in the shadow of COVID-19.

Therapeutic Efficacy and Resistance Selection of a Lipopeptide Fusion Inhibitor in Simian Immunodeficiency Virus-Infected Rhesus Macaques.

We recently reported a group of lipopeptide-based membrane fusion inhibitors with potent antiviral activities against human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV). In this study, the in vivo therapeutic efficacy of such a lipopeptide, LP-52, was evaluated in rhesus macaques chronically infected with pathogenic SIVmac239. In a pilot study with one monkey, monotherapy with low-dose LP-52 rapidly reduced the plasma viral loads to below the limit of detection and maintained viral suppression during three rounds of structurally interrupted treatment. The therapeutic efficacy of LP-52 was further verified in four infected monkeys; however, three out of the monkeys had viral rebounds under the LP-52 therapy. We next focused on characterizing SIV mutants responsible for the in vivo resistance. Sequence analyses revealed that a V562A or V562M mutation in the N-terminal heptad repeat (NHR) and a E657G mutation in the C-terminal heptad repeat (CHR) of SIV gp41 conferred high resistance to LP-52 and cross-resistance to the peptide drug T20 and two newly designed lipopeptides (LP-80 and LP-83). Moreover, we showed that the resistance mutations greatly reduced the stability of diverse fusion inhibitors with the NHR site, and V562A or V562M in combination with E657G could significantly impair the functionality of viral envelopes (Envs) to mediate SIVmac239 infection and decrease the thermostability of viral six-helical bundle (6-HB) core structure. In conclusion, the present data have not only facilitated the development of novel anti-HIV drugs that target the membrane fusion step, but also help our understanding of the mechanism of viral evolution to develop drug resistance.IMPORTANCE The anti-HIV peptide drug T20 (enfuvirtide) is the only membrane fusion inhibitor available for treatment of viral infection; however, it exhibits relatively weak antiviral activity, short half-life, and a low genetic barrier to inducing drug resistance. Design of lipopeptide-based fusion inhibitors with extremely potent and broad antiviral activities against divergent HIV-1, HIV-2, and SIV isolates have provided drug candidates for clinical development. Here, we have verified a high therapeutic efficacy for the lipopeptide LP-52 in SIVmac239-infected rhesus monkeys. The resistance mutations selected in vivo have also been characterized, providing insights into the mechanism of action of newly designed fusion inhibitors with a membrane-anchoring property. For the first time, the data show that HIV-1 and SIV can share a similar genetic pathway to develop resistance, and that a lipopeptide fusion inhibitor could have a same resistance profile as its template peptide.

Monotherapy with a low-dose lipopeptide HIV fusion inhibitor maintains long-term viral suppression in rhesus macaques.

Combination antiretroviral therapy (cART) dramatically improves survival of HIV-infected patients, but lifelong treatment can ultimately result in cumulative toxicities and drug resistance, thus necessitating the development of new drugs with significantly improved pharmaceutical profiles. We recently found that the fusion inhibitor T-20 (enfuvirtide)-based lipopeptides possess dramatically increased anti-HIV activity. Herein, a group of novel lipopeptides were designed with different lengths of fatty acids, identifying a stearic acid-modified lipopeptide (LP-80) with the most potent anti-HIV activity. It inhibited a large panel of divergent HIV subtypes with a mean IC50 in the extremely low picomolar range, being > 5,300-fold more active than T-20 and the neutralizing antibody VRC01. It also sustained the potent activity against T-20-resistant mutants and exhibited very high therapeutic selectivity index. Pharmacokinetics of LP-80 in rats and monkeys verified its potent and long-acting anti-HIV activity. In the monkey, subcutaneous administration of 3 mg/kg LP-80 yielded serum concentrations of 1,147 ng/ml after injection 72 h and 9 ng/ml after injection 168 h (7 days), equivalent to 42,062- and 330-fold higher than the measured IC50 value. In SHIV infected rhesus macaques, a single low-dose LP-80 (3 mg/kg) sharply reduced viral loads to below the limitation of detection, and twice-weekly monotherapy could maintain long-term viral suppression.

Immunization with HIV-1 gp41 subunit virosomes induces mucosal antibodies protecting nonhuman primates against vaginal SHIV challenges.

Human immunodeficiency virus (HIV)-1 is mainly transmitted mucosally during sexual intercourse. We therefore evaluated the protective efficacy of a vaccine active at mucosal sites. Macaca mulatta monkeys were immunized via both the intramuscular and intranasal routes with an HIV-1 vaccine made of gp41-subunit antigens grafted on virosomes, a safe delivery carrier approved in humans with self-adjuvant properties. Six months after 13 vaginal challenges with simian-HIV (SHIV)-SF162P3, four out of five vaccinated animals remained virus-negative, and the fifth was only transiently infected. None of the five animals seroconverted to p27gag-SIV. In contrast, all 6 placebo-vaccinated animals became infected and seroconverted. All protected animals showed gp41-specific vaginal IgAs with HIV-1 transcytosis-blocking properties and vaginal IgGs with neutralizing and/or antibody-dependent cellular-cytotoxicity activities. In contrast, plasma IgGs totally lacked virus-neutralizing activity. The protection observed challenges the paradigm whereby circulating antiviral antibodies are required for protection against HIV-1 infection and may serve in designing a human vaccine against HIV-1-AIDS.

Reduction of peak viremia by an integration-defective SIV proviral DNA vaccine in rhesus macaques.

An integrase-defective SIV (idSIV) vaccine delivered by a DNA prime and viral particle boost approach can suppress viral loads (VLs) during the acute infection stage after intravenous SIVmac239 challenge. This study investigated how idSIV DNA and viral particle immunization alone contributed to the suppression of VLs in Chinese rhesus macaques after SIV challenge. Two macaques were immunized with idSIV DNA five times and two macaques were immunized with idSIV viral particles three times. Cellular and humoral immune responses were measured in the vaccinated macaques after immunization. The VLs and CD4+ T cell counts were monitored for 28 weeks after the intravenous SIVmac239 challenge. The SIV-specific T cell responses were only detected in the DNA-vaccinated macaques. However, binding and neutralizing antibodies against autologous and heterologous viruses were moderately better in macaques immunized with viral particles than in macaques immunized with DNA. After the challenge, the mean peak viremia in the DNA group was 2.3 logs lower than that in the control group, while they were similar between the viral particle immunization and control groups. Similar CD4+ T cell counts were observed among all groups. These results suggest that idSIV DNA immunization alone reduces VLs during acute infection after SIV challenge in macaques and may serve as a key component in combination with other immunogens as prophylactic vaccines.

Probiotics protect against tenofovir-induced mandibular bone loss in mice by rescuing mandible-derived mesenchymal stem cell proliferation and osteogenic differentiation.

BACKGROUND: Tenofovir disoproxil fumarate (TDF), a primary antiretroviral agent used to treat AIDS, triggers systematic bone loss. However, the effect of TDF on osteopenia or osteoporosis in the jaw remains unclear. TDF-induced bone loss in the jaw, if any, likely involves mandible-derived mesenchymal stem cells (MMSCs), which play a key role in jawbone metabolism. Probiotics prevent long bone loss, and could prove efficacious in treating TDF-induced mandibular bone loss. OBJECTIVES: To determine whether TDF triggers mandibular bone loss, elucidate the underlying mechanisms, and study the effect of Lactobacillus rhamnosus GG (LGG) on TDF-induced bone loss in the jaw. METHODS: Tenofovir disoproxil fumarate was administered orally daily and LGG semiweekly from eight weeks to the end of the study (LGG group) to male C57BL6/J mice. The mice were sacrificed, and body weight (BW) and serum Ca and P were measured. Mandibular histomorphometry was evaluated by micro-CT. MMSCs and LGG culture supernatants were isolated, and MMSC proliferation and ALP production when treated with different concentrations of LGG supernatant and/or TDF were measured. Relative abundance of osteogenic markers was assessed by qPCR. RESULTS: Orally administered LGG protected against bone mass loss and deterioration of bone microarchitecture and increased serum P levels. The BW of the TDF group was highest among the study groups. TDF partially impaired osteogenesis and proliferation of MMSCs. LGG culture supernatant rescued MMSC osteogenesis and proliferation, and osteogenic gene expression. CONCLUSIONS: Lactobacillus rhamnosus GG protected against tenofovir-induced mandibular bone loss in mice by rescuing MMSC proliferation and osteogenesis.

Design of Novel HIV-1/2 Fusion Inhibitors with High Therapeutic Efficacy in Rhesus Monkey Models.

T-20 (enfuvirtide) is the only approved viral fusion inhibitor that is used for the treatment of human immunodeficiency virus type 1 (HIV-1) infection; however, it has relatively low antiviral activity and easily induces drug resistance. We recently reported a T-20-based lipopeptide fusion inhibitor (LP-40) showing improved anti-HIV activity (X. Ding et al., J Virol 91:e00831-17, 2017, https://doi.org/10.1128/JVI.00831-17). In this study, we designed LP-50 and LP-51 by refining the structure and function of LP-40. The two new lipopeptides showed dramatically enhanced secondary structure and binding stability and were exceptionally potent inhibitors of HIV-1, HIV-2, simian immunodeficiency virus (SIV), and chimeric simian-human immunodeficiency virus (SHIV), with mean 50% inhibitory concentrations (IC50s) in the very low picomolar range. They also exhibited dramatically increased potencies in inhibiting a panel of T-20- and LP-40-resistant mutant viruses. In line with their in vitro data, LP-50 and LP-51 exhibited extremely potent and long-lasting ex vivo anti-HIV activities in rhesus monkeys: serum dilution peaks that inhibited 50% of virus infection were >15,200-fold higher than those for T-20 and LP-40. Low-dose, short-term monotherapy of LP-51 could sharply reduce viral loads to undetectable levels in acutely and chronically SHIV infected monkey models. To our knowledge, LP-50 and LP-51 are the most potent and broad HIV-1/2 and SIV fusion inhibitors, which can be developed for clinical use and can serve as tools for exploration of the mechanisms of viral entry and inhibition.IMPORTANCE T-20 remains the only membrane fusion inhibitor available for the treatment of viral infection, but its relatively low anti-HIV activity and genetic barrier for drug resistance have significantly limited its clinical application. Here we report two new lipopeptide-based fusion inhibitors (LP-50 and LP-51) showing extremely potent inhibitory activities against diverse HIV-1, HIV-2, SIV, and T-20-resistant variants. Promisingly, both inhibitors exhibited potent and long-lasting ex vivo anti-HIV activity and could efficiently suppress viral loads to undetectable levels in SHIV-infected monkey models. We believe that LP-50 and LP-51 are the most potent and broad-spectrum fusion inhibitors known to date and thus have high potential for clinical development.

CD45RO regulates the HIV-1 gp120-mediated apoptosis of T cells by activating Lck.

CD45 has been reported to regulate the HIV-1 gp120-induced apoptosis of Jurkat cells. Here, we demonstrate that the extracellular domain of CD45 plays an important role in this function. We observed that CD45RO-transfected cells, but not cells transfected with other CD45 isoforms, underwent significant apoptosis induced by gp120. However, a CD45RA-transfected cell line treated with an O-glycan inhibitor was able to undergo apoptosis. The role of the extracellular domain of CD45 was further confirmed using CD45 isoform-transfected cell lines by analyzing the phosphorylation of Lck, which is a direct substrate of CD45 tyrosine phosphatase, and by using an Lck inhibitor. These results suggest that CD45RO modulates HIV-1 gp120-induced apoptosis by regulating the activity of Lck.

A Lipopeptide HIV-1/2 Fusion Inhibitor with Highly Potent In Vitro, Ex Vivo, and In Vivo Antiviral Activity.

Peptides derived from the C-terminal heptad repeat (CHR) region of the human immunodeficiency virus type 1 (HIV-1) fusogenic protein gp41 are potent viral entry inhibitors, and currently, enfuvirtide (T-20) is the only one approved for clinical use; however, emerging drug resistance largely limits its efficacy. In this study, we generated a novel lipopeptide inhibitor, named LP-19, by integrating multiple design strategies, including an N-terminal M-T hook structure, an HIV-2 sequence, intrahelical salt bridges, and a membrane-anchoring lipid tail. LP-19 showed stable binding affinity and highly potent, broad, and long-lasting antiviral activity. In in vitro studies, LP-19 efficiently inhibited HIV-1-, HIV-2-, and simian immunodeficiency virus (SIV)-mediated cell fusion, viral entry, and infection, and it was highly active against diverse subtypes of primary HIV-1 isolates and inhibitor-resistant mutants. Ex vivo studies demonstrated that LP-19 exhibited dramatically increased anti-HIV activity and an extended half-life in rhesus macaques. In short-term monotherapy, LP-19 reduced viral loads to undetectable levels in acutely and chronically simian-human immunodeficiency virus (SHIV)-infected monkeys. Therefore, this study offers an ideal HIV-1/2 fusion inhibitor for clinical development and emphasizes the importance of the viral fusion step as a drug target.IMPORTANCE The peptide drug T-20 is the only viral fusion inhibitor in the clinic, which is used for combination therapy of HIV-1 infection; however, it requires a high dosage and easily induces drug resistance, calling for a new drug with significantly improved pharmaceutical profiles. Here, we have developed a short-lipopeptide-based fusion inhibitor, termed LP-19, which mainly targets the conserved gp41 pocket site and shows highly potent inhibitory activity against HIV-1, HIV-2, and even SIV isolates. LP-19 exhibits dramatically increased antiviral activity and an extended half-life in rhesus macaques, and it has potent therapeutic efficacy in SHIV-infected monkeys, highlighting its high potential as a new viral fusion inhibitor for clinical use.

Correlation of central memory CD4+ T-Cell decrease in the peripheral blood with disease progression in SIVmac251-infected Chinese rhesus macaques.

BACKGROUND: Correlation of CD4(+) Tcm cells in the peripheral blood to disease progression in SIVmac251 infection was examined in Chinese rhesus macaques. METHODS: Plasma viral RNA loads were measured by a quantitative real-time reverse transcription-PCR (qRT-PCR) assay for SIV gag. Disease progression was determined based on time of survival. Phenotyping of CD4(+) T-cell subsets in the peripheral blood was longitudinally performed by flow cytometry. RESULTS: Although CD4(+) T-cell decrease and low CD4(+)/CD8(+) T-cell ratio in the peripheral blood after SIVmac251 infection did not correlate with disease progression, CD4(+) Tcm cell decrease was observed to be correlated to disease progression in the SIVmac251-infected Chinese rhesus macaques. CONCLUSIONS: Our findings suggest that CD4(+) Tcm cell decrease could be used as a predictive marker for defining the pathogenesis of the SIV disease and consequently HIV/SIV vaccine efficacy in Chinese rhesus macaques.

Organization and management of the treatment for the wounded in 8.12 Tinjin Port Explosion, China.

Tianjin Medical University General Hospital treated 233 wounded in 8.12 Tinjin Port explosion. Here we would like to analyze the treatment process for the wounded, and share the experiences of orga- nization and management for emergency rescue operation.

Comparison of viral burden and disease progression in Chinese-origin rhesus macaques infected with common experimentally applied chimeric virus: SHIV-1157ipd3N4, SHIV-162P3, or SHIV-KB9.

BACKGROUND: Little is known about the comparative susceptibility and differential pathogenic characteristics of Chinese-origin rhesus macaques upon infection with the chimeric SHIVs most commonly applied in experimental research. METHODS: In vivo infectivity, viral replication, and disease progression related to SHIV-1157ipd3N4, SHIV-162P3, and SHIV-KB9 infections were assessed after intravenous inoculation of Chinese-origin rhesus macaques (n = 10 each). RESULTS: SHIV-KB9-infected monkeys had higher plasma viral loads than those infected with SHIV-1157ipd3N4 or SHIV-162P3 (P < 0.05). The SHIV-KB9 group had a member that progressed rapidly to simian acquired immunodeficiency syndrome and was moribund at 155 days post-inoculation. SHIV-KB9 and SHIV-162P3 showed reverse trends in the effects on levels of memory T-cell subpopulations. CONCLUSIONS: This study provides foundational data for future efficacy testing of candidate vaccine and antiviral therapy using a Chinese-origin rhesus macaque system.

Prophylactic and therapeutic effect of AZT/3TC in RT-SHIV infected Chinese-origin rhesus macaques.

BACKGROUND: The precise efficacy of nucleoside analogue reverse-transcriptase inhibitors (NRTIs) in preventing and inhibiting virus replication remains unknown in RT-SHIV infected Chinese-origin rhesus macaques (Ch RM). FINDINGS: Ch RM were inoculated intravenously with 200 TCID50 RT-SHIV and treated by gavage with NRTIs (20 mg AZT and 10 mg 3TC twice per day) for four consecutive weeks beginning at one hour, on day 217 or 297 post inoculation, respectively. Treatment with AZT/3TC inhibited transiently RT-SHIV replication during chronic infection, but did not significantly affect peripheral blood CD4+ T cells in macaques. Treatment with AZT/3TC at 1 hour post infection prevented RT-SHIV infection in two out of four animals during the 120-day observation period. CONCLUSIONS: Therefore, the Ch RM model with RT-SHIV infection can be used to evaluate the efficacy of new NRTIs.

Circulating IL-21 levels increase during early simian-human immunodeficiency virus infection in macaques.

The cytokine interleukin-21 (IL-21) regulates viral pathogenesis in individuals infected with human and simian immunodeficiency viruses. However, because the time of initial infection with HIV in humans is rarely known, the dynamics of IL-21 production during the first weeks have not been adequately explored. In the present study, we used rhesus macaques to model the first stages of infection. Twenty-two rhesus macaques were infected rectally with simian-human immunodeficiency virus (SHIV)-1157ipd3N4, and for 12 weeks, replication of the virus, the numbers of CD4+ and CD8+ T cells, and the levels of plasma IL-21 were monitored. Our study demonstrated that plasma levels of IL-21 increased during the early phase of SHIV infection when compared with the values observed before inoculation. We conclude that IL-21 has a likely role in the immunopathogenesis of HIV/SIV/SHIV.

[Establishment and identification of a C57B/6 mouse sarcoidosis granuloma model].

OBJECTIVE: To establish a C57BL/6 mouse sarcoidosis granuloma model elicited by mycobacterial superoxide dismutase A peptide (SodA). METHODS: Thirty female C57BL/6 mice were randomly divided equally into 5 groups: a combination (SodA+Sepharose) group, a SodA group, a IFA (incomplete Freund's adjuvant) group, a sepharose group and a blank control group. On the first day, the combination group and the SodA group were sensitized by subcutaneous injection of 50 µg SodA incorporated into IFA 0.25 ml. The IFA group and the Sepharose group were treated with subcutaneous injection of IFA 0.25 ml and PBS 0.25 ml respectively, while the blank control group was not given any treatment. On the 14th day, the combination group was challenged by tail vein injection of 50 µg SodA covalently coupled to 6000 agarose 4B beads (in PBS 0.5 ml) . The SodA group was challenged by tail-vein injection of 50 µg SodA (in PBS 0.5 ml) . The IFA group and the Sepharose group were treated by tail-vein injection of 6000 agarose 4B beads (in PBS 0.5 ml) , while the blank control group was not given any treatment. On the 22th day, the mice were dissected and the gross and pathological changes of lymph nodes and lungs were observed. Immunohistochemisty was used to identify Mac-2 and CD(+)4T in granuloma. Counts and differentials of BALF cells were measured. CD(+)4/CD(+)8 in BALF and cytokines (IFN-γ and IL-12 ) levels in the lungs were detected by flow cytometry. RESULTS: Enlargement of peripheral and pulmonary hilar lymph nodes were found in the combination group and the SodA group, and sarcoidosis granuloma was found in the lymph nodes and lungs of the combination group. Sarcoidosis granuloma was also found in the lymph nodes but not in the lungs of the SodA group. No sarcoidosis granuloma was observed in the lungs and lymph nodes of the IFA group, the Sepharose group and the blank control group. Macrophage specific antigen Mac-2 and CD(+)4T were positive in the core and rim of the granuloma respectively. The lymphocyte percentages in the BALF of the combination group and the SodA group [(19.4 ± 6.5)% and (22.3 ± 8.5)%] were significantly higher than that in the IFA group, the Sepharose group and the blank control group [(8.5 ± 4.3)%, (7.7 ± 3.4)%, (0.8 ± 0.6%)] (P < 0.05 ). CD(+)4/CD(+)8 in the BALF of the combination group and the SodA group (3.5 ± 1.4, 3.2 ± 1.1) were significantly higher than that in the IFA group and the Sepharose group (1.2 ± 0.5, 1.0 ± 0.4) (P < 0.05 ). IFN-γ and IL-12 in the lungs of the combination group and the SodA group [IFN-γ:(32.9 ± 9.7) ng/L, (26.4 ± 7.2) ng/L; IL-12: (29.6 ± 9.4) ng/L, (26.1 ± 8.9) ng/L]were significantly higher than those of the IFA group, the Sepharose group and the blank control group [IFN-γ: (16.5 ± 6.8) ng/L, (12.2 ± 5.0) ng/L, (9.0 ± 2.6) ng/L; IL-12: (16.7 ± 4.6) ng/L, (13.6 ± 4.4) ng/L, (9.6 ± 5.3) ng/L] (P < 0.05 ). But these indexes were not significantly different between the combination group and the SodA group, and among the IFA group, the Sepharose group and the blank control group (P > 0.05). CONCLUSION: SodA can elicit sarcoidosis granuloma in C57BL/6 mice, and the immunological features of the model were similar to those in human sarcoidosis.

TLR7 Agonist GS-9620 Combined with Nicotinamide Generate Viral Reactivation in Seronegative SHIVSF162P3-Infected Rhesus Monkeys.

Antiretroviral therapy is capable of inhibiting HIV replication, but it fails to completely achieve a cure due to HIV persistence. The commonly used HIV cure approach is the "shock and kill" strategy, which employs latency-reversing agents to trigger viral reactivation and boost cellular immunity. Finding the appropriate drug combination for the "shock and kill" strategy would greatly facilitate clinical trials. The toll-like receptor (TLR) 7 agonist GS-9620 and nicotinamide (NAM) are reported as potential latency-reversing agents. Herein, we found the absence of viral reactivation when SHIVSF162P3-aviremic rhesus macaques were treated with GS-9620 monotherapy. However, our findings demonstrate that viral blips emerged in half of the macaques treated with the combination therapy of GS-9620 and NAM. Notably, an increase in the reactivation of the replication-competent latent virus was measured in monkeys treated with the combination therapy. These findings suggest that the GS-9620 and NAM combination could be used as a multipronged HIV latency stimulation approach, with potential for optimizing antiviral therapy design.

Modified extended object tracker for 2D lidar data using random matrix model.

The random matrix (RM) model is a typical extended object-modeling method that has been widely used in extended object tracking. However, existing RM-based filters usually assume that the measurements follow a Gaussian distribution, which may lead to a decrease in accuracy when the filter is applied to the lidar system. In this paper, a new observation model used to modify an RM smoother by considering the characteristics of 2D LiDAR data is proposed. Simulation results show that the proposed method achieves a better performance than the original RM tracker in a 2D lidar system.