Global prevalence and burden of multidrug-resistant tuberculosis from 1990 to 2019.

BACKGROUND: Tuberculosis(TB) remains a pressing public health challenge, with multidrug-resistant tuberculosis (MDR-TB) emerging as a major threat. And healthcare authorities require reliable epidemiological evidence as a crucial reference to address this issue effectively. The aim was to offer a comprehensive epidemiological assessment of the global prevalence and burden of MDR-TB from 1990 to 2019. METHODS: Estimates and 95% uncertainty intervals (UIs) for the age-standardized prevalence rate (ASPR), age-standardized incidence rate (ASIR), age-standardized disability-adjusted life years rate (ASR of DALYs), and age-standardized death rate (ASDR) of MDR-TB were obtained from the Global Burden of Disease (GBD) 2019 database. The prevalence and burden of MDR-TB in 2019 were illustrated in the population and regional distribution. Temporal trends were analyzed by using Joinpoint regression analysis to calculate the annual percentage change (APC), average annual percentage change (AAPC) and its 95% confidence interval(CI). RESULTS: The estimates of the number of cases were 687,839(95% UIs: 365,512 to 1223,262), the ASPR were 8.26 per 100,000 (95%UIs: 4.61 to 15.20), the ASR of DALYs were 52.38 per 100,000 (95%UIs: 22.64 to 97.60) and the ASDR were 1.36 per 100,000 (95%UIs: 0.54 to 2.59) of MDR-TB at global in 2019. Substantial burden was observed in Africa and Southeast Asia. Males exhibited higher ASPR, ASR of DALYs, and ASDR than females across most age groups, with the burden of MDR-TB increasing with age. Additionally, significant increases were observed globally in the ASIR (AAPC = 5.8; 95%CI: 5.4 to 6.1; P < 0.001), ASPR (AAPC = 5.9; 95%CI: 5.4 to 6.4; P < 0.001), ASR of DALYs (AAPC = 4.6; 95%CI: 4.2 to 5.0; P < 0.001) and ASDR (AAPC = 4.4; 95%CI: 4.0 to 4.8; P < 0.001) of MDR-TB from 1990 to 2019. CONCLUSIONS: This study underscored the persistent threat of drug-resistant tuberculosis to public health. It is imperative that countries and organizations worldwide take immediate and concerted action to implement measures aimed at significantly reducing the burden of TB.

Global prevalence, burden and trend in HIV and drug-susceptible tuberculosis co-infection from 1990 to 2019 and prediction to 2040.

Objectives: The purpose of this study is to describe the current situation and forecast the trends of co-infection between the human immunodeficiency virus (HIV) and drug-susceptible tuberculosis (DS-TB) in different countries, across various age groups and genders. Methods: We obtained data on the number of cases, age-standardized incidence rate, age-standardized prevalence rate, age-standardized rate of disability-adjusted life years (DALYs), and age-standardized death rate from the Global Burden of Disease (GBD) 2019 database. These data were used to describe the distribution and burden of co-infection between the human immunodeficiency virus (HIV) and DS-TB in different regions, genders, and age groups. We employed joinpoint regression analysis to analyze the temporal trends from 1990 to 2019. Additionally, an age-period-cohort model was established to forecast the future trends of co-infection up to 2040. Results: The prevalence and burden of co-infection varied across different age groups and genders. The territories with the higher disease burden were distributed in some Asian and African countries. In terms of temporal trends, the age-standardized incidence rate and age-standardized prevalence rate of HIV and DS-TB co-infection exhibited an overall increasing trend from 1990 to 2019, and the prediction indicated a slow downward trend from 2019 to 2040. Conclusions: The co-infection of HIV and DS-TB posed a grave threat to public health and economic development. What's more, there existed a significant disparity between the actual state of co-infection and the desired goals for prevention and control.

Daytime and nighttime high temperatures differentially increased the risk of cardiovascular disease: A nationwide hospital-based study in China.

Short-term exposure to ambient high temperature (heat) could increase the risk of cardiovascular disease (CVD). However, available evidence on the burden of daytime and nighttime heat on CVD is limited and vulnerable populations remain unknown so far. We aimed to examine and differentiate the impact of daytime and nighttime heat on CVD in China. Data on daily outpatient visits for CVD were collected from 15 Chinese cities spanning multiple geographical regions, climates, and socio-economic conditions. The population-weighted temperature was used to calculate excess heat exposure in warm seasons (June-September) from 2011 to 2015. Hot day excess (HDE) and hot night excess (HNE), the sum of temperature above the heat threshold during daytime and nighttime respectively, were used to represent daytime and nighttime excess heat. A distributed lag non-linear model was employed to estimate the city-level association between HDE/HNE and daily CVD cases. The city-level association was then pooled by multivariate meta-analysis. We further estimated the disease burden of CVD attributable to HDE and HNE by geographical regions, gender, and age. A total of 729,409 cases of CVD were included in this study. Both HDE and HNE were associated with an increased risk of CVD, with greater effects from nighttime heat (relative risk (RR): 1.38; 95% confidence interval (CI): 1.18-1.61) than daytime heat (RR: 1.10; 95% CI: 1.05-1.15). The proportion of CVD cases attributable to HNE was 15.7%, which was almost three times as high as HDE (4.6%, p for difference <0.05). Males, people living in northern cities, and those aged less than 45 years were more vulnerable to HNE. Our findings for the first time revealed an intra-day difference in the heat effect on CVD, with a greater impact from nighttime heat exposure, which should be considered to protect vulnerable populations on hot days.

Using ecological niche modeling to predict the potential distribution of scrub typhus in Fujian Province, China.

BACKGROUND: Despite the increasing number of cases of scrub typhus and its expanding geographical distribution in China, its potential distribution in Fujian Province, which is endemic for the disease, has yet to be investigated. METHODS: A negative binomial regression model for panel data mainly comprising meteorological, socioeconomic and land cover variables was used to determine the risk factors for the occurrence of scrub typhus. Maximum entropy modeling was used to identify the key predictive variables of scrub typhus and their ranges, map the suitability of different environments for the disease, and estimate the proportion of the population at different levels of infection risk. RESULTS: The final multivariate negative binomial regression model for panel data showed that the annual mean normalized difference vegetation index had the strongest correlation with the number of scrub typhus cases. With each 0.1% rise in shrubland and 1% rise in barren land there was a 75.0% and 37.0% increase in monthly scrub typhus cases, respectively. In contrast, each unit rise in mean wind speed in the previous 2 months and each 1% increase in water bodies corresponded to a decrease of 40.0% and 4.0% in monthly scrub typhus cases, respectively. The predictions of the maximum entropy model were robust, and the average area under the curve value was as high as 0.864. The best predictive variables for scrub typhus occurrence were population density, annual mean normalized difference vegetation index, and land cover types. The projected potentially most suitable areas for scrub typhus were widely distributed across the eastern coastal area of Fujian Province, with highly suitable and moderately suitable areas accounting for 16.14% and 9.42%, respectively. Of the total human population of the province, 81.63% reside in highly suitable areas for scrub typhus. CONCLUSIONS: These findings could help deepen our understanding of the risk factors of scrub typhus, and provide information for public health authorities in Fujian Province to develop more effective surveillance and control strategies in identified high risk areas in Fujian Province.

Spatiotemporal dynamics and environmental determinants of scrub typhus in Anhui Province, China, 2010-2020.

This study aims to describe the epidemiological characteristics of scrub typhus, detect the spatio-temporal patterns of scrub typhus at county level, and explore the associations between the environmental variables and scrub typhus cases in Anhui Province. Time-series analysis, spatial autocorrelation analysis, and space-time scan statistics were used to explore the characteristics and spatiotemporal patterns of the scrub typhus in Anhui Province. Negative binomial regression analysis was used to explore the association between scrub typhus and environmental variables. A total of 16,568 clinically diagnosed and laboratory-confirmed cases were reported from 104 counties of 16 prefecture-level cities. The number of female cases was higher than male cases, with a proportion of 1.32:1. And the proportion of cases over 65 years old was the highest, accounting for 33.8% of the total cases. Two primary and five secondary high-risk clusters were detected in the northwestern, northeastern, and central-eastern parts of Anhui Province. The number of cases in primary and secondary high-risk clusters accounted for 60.27% and 3.00%, respectively. Scrub typhus incidence in Anhui Province was positively correlated with the population density, normalized difference vegetation index, and several meteorological variables. The mean monthly sunshine duration with 3 lags (SSD_lag3), mean monthly ground surface temperature with 1 lag (GST_lag1), and mean monthly relative humidity with 3 lags (RHU_lag3) had the most significant association with increased cases of scrub typhus. Our findings indicate that public health interventions need to be focused on the elderly farmers in north of the Huai River in Anhui Province.

The association between air pollutants, meteorological factors and tuberculosis cases in Beijing, China: A seven-year time series study.

BACKGROUND: Tuberculosis (TB) is a severe public health problem globally. Previous studies have revealed insufficient and inconsistent associations between air pollutants, meteorological factors and TB cases. Yet few studies have examined the associations between air pollutants, meteorological factors and TB cases in Beijing. OBJECTIVE: The purpose of this study was to explore the impact of air pollutants and meteorological factors on TB in Beijing, and to provide novel insights into public health managers to formulate control strategies of TB. METHODS: Data on the daily case of TB in Beijing during 2014-2020 were obtained from Chinese tuberculosis information management system. Concurrent data on the daily PM10, PM2.5, SO2, NO2, CO and O3, were obtained from the online publication platform of the Chinese National Environmental Monitoring Center. Daily average temperature, average wind speed, relative humidity, sunshine duration and total precipitation were collected from the China Meteorological Science Data Sharing Service System. A distributed lag non-linear model was fitted to identify the non-linear exposure-response relationship and the lag effects between air pollutions, meteorological factors and TB cases in Beijing. RESULTS: In the single-factor model, the excess risk (ER) of TB was significantly positively associated with every 10 µg/m3 increase in NO2 in lag 1 week (ER: 1.3%; 95% confidence interval [CI]: 0.4%, 2.3%) and every 0.1 m/s increase in average wind speed in lag 5 weeks (ER: 0.3%; 95% CI: 0.1%, 0.5%), and was negatively associated with every 10 µg/m3 increase in O3 in lag 1 week (ER: -1.2%; 95% CI: -1.8%, -0.5%), every 5 °C increase in average temperature (ER: -1.7%; 95% CI: -2.9%, -0.4%) and every 10% increase in average relative humidity (ER: -0.4%; 95% CI: -0.8%, -0.1%) in lag 10 weeks, respectively. In the multi-factor model, the lag effects between TB cases and air pollutants, meteorological factors were similar. The subgroup analysis suggests that the effects of NO2, O3, average wind speed and relative humidity on TB were greater in male or labor age subgroup, while the effect of CO was greater in the elderly. In addition, no significant associations were found between PM2.5, SO2, sunshine duration and TB cases. CONCLUSION: Our findings provide a better understanding of air pollutants and meteorological factors driving tuberculosis occurrence in Beijing, which enhances the capacity of public health manager to target early warning and disease control policy-making.

Spatial-temporal dynamics and time series prediction of HFRS in mainland China: A long-term retrospective study.

Hemorrhagic fever with renal syndrome (HFRS) is highly endemic in mainland China. The current study aims to characterize the spatial-temporal dynamics of HFRS in mainland China during a long-term period (1950-2018). A total of 1 665 431 cases of HFRS were reported with an average annual incidence of 54.22 cases/100 000 individuals during 1950-2018. The joint regression model was used to define the global trend of the HFRS cases with an increasing-decreasing-slightly increasing-decreasing-slightly increasing trend during the 68 years. Then spatial correlation analysis and wavelet cluster analysis were used to identify four types of clusters of HFRS cases located in central and northeastern China. Lastly, the prophet model outperforms auto-regressive integrated moving average model in the HFRS modeling. Our findings will help reduce the knowledge gap on the transmission dynamics and distribution patterns of the HFRS in mainland China and facilitate to take effective preventive and control measures for the high-risk epidemic area.

Co-effects of global climatic dynamics and local climatic factors on scrub typhus in mainland China based on a nine-year time-frequency analysis.

Background: Scrub Typhus (ST) is a rickettsial disease caused by Orientia tsutsugamushi. The number of ST cases has been increasing in China during the past decades, which attracts great concerns of the public health. Methods: We obtained monthly documented ST cases greater than 54 cases in 434 counties of China during 2012-2020. Spatiotemporal wavelet analysis was conducted to identify the ST clusters with similar pattern of the temporal variation and explore the association between ST variation and El Niño and La Niña events. Wavelet coherency analysis and partial wavelet coherency analysis was employed to further explore the co-effects of global and local climatic factors on ST. Results: Wavelet cluster analysis detected seven clusters in China, three of which are mainly distributed in Eastern China, while the other four clusters are located in the Southern China. Among the seven clusters, summer and autumn-winter peak of ST are the two main outbreak periods; while stable and fluctuated periodic feature of ST series was found at 12-month and 4-(or 6-) month according to the wavelet power spectra. Similarly, the three-character bands were also found in the associations between ST and El Niño and La Niña events, among which the 12-month period band showed weakest climate-ST association and the other two bands owned stronger association, indicating that the global climate dynamics may have short-term effects on the ST variations. Meanwhile, 12-month period band with strong association was found between the four local climatic factors (precipitation, pressure, relative humidity and temperature) and the ST variations. Further, partial wavelet coherency analysis suggested that global climatic dynamics dominate annual ST variations, while local climatic factors dominate the small periods. Conclusion: The ST variations are not directly attributable to the change in large-scale climate. The existence of these plausible climatic determinants stimulates the interests for more insights into the epidemiology of ST, which is important for devising prevention and early warning strategies.

Epidemiological characteristics and spatiotemporal patterns of scrub typhus in Fujian province during 2012-2020.

BACKGROUND: Scrub typhus has become a serious public health concern in the Asia-Pacific region including China. There were new natural foci continuously recognized and dramatically increased reported cases in mainland China. However, the epidemiological characteristics and spatiotemporal patterns of scrub typhus in Fujian province have yet to be investigated. OBJECTIVE: This study proposes to explore demographic characteristics and spatiotemporal dynamics of scrub typhus cases in Fujian province, and to detect high-risk regions between January 2012 and December 2020 at county/district scale and thereby help in devising public health strategies to improve scrub typhus prevention and control measures. METHOD: Monthly cases of scrub typhus reported at the county level in Fujian province during 2012-2020 were collected from the National Notifiable Disease Surveillance System. Time-series analyses, spatial autocorrelation analyses and space-time scan statistics were applied to identify and visualize the spatiotemporal patterns of scrub typhus cases in Fujian province. The demographic differences of scrub typhus cases from high-risk and low-risk counties in Fujian province were also compared. RESULTS: A total of 11,859 scrub typhus cases reported in 87 counties from Fujian province were analyzed and the incidence showed an increasing trend from 2012 (2.31 per 100,000) to 2020 (3.20 per 100,000) with a peak in 2018 (4.59 per 100,000). There existed two seasonal peaks in June-July and September-October every year in Fujian province. A significant positive spatial autocorrelation of scrub typhus incidence in Fujian province was observed with Moran's I values ranging from 0.258 to 0.471 (P<0.001). Several distinct spatiotemporal clusters mainly concentrated in north and southern parts of Fujian province. Compared to low-risk regions, a greater proportion of cases were female, farmer, and older residents in high-risk counties. CONCLUSIONS: These results demonstrate a clear spatiotemporal heterogeneity of scrub typhus cases in Fujian province, and provide the evidence in directing future researches on risk factors and effectively assist local health authorities in the refinement of public health interventions against scrub typhus transmission in the high risk regions.

Peripheral blood mononuclear cell traffic plays a crucial role in mother-to-infant transmission of hepatitis B virus.

The role of peripheral blood mononuclear cells (PBMCs) in HBV intrauterine infection is not fully defined. Particularly the origin of PBMCs in HBV-infected neonates remains to be addressed. We carried out a population-based nested case-control study by enrolling 312 HBsAg-positive mothers and their babies. PBMC HBV DNA as well as serum HBsAg and HBV DNA was tested in cohort entry samples. Totally, 45.5% (142/312) of the newborns were found to be infected with HBV in perinatal transmission. 119 mother-infant pairs were identified to be different in the genetic profile of maternal and fetal PBMCs by AS-PCR and hemi-nested PCR. Among them, 57.1% (68/119) of the maternal PBMCs in index cases were positive for HBV DNA while 83.8% (57/68) of the HBV DNA positive maternal PBMCs passed the placental barrier and entered the fetus. Furthermore, maternal PBMC HBV infection was significantly associated with newborn infants HBV infection. PBMC traffic from mother to fetus resulted in a 9.5-fold increased risk of HBV infection in PBMC HBV DNA positive newborn infants. These data indicate that maternal PBMCs infected with HBV contribute to HBV intrauterine infection of newborn infants via PBMC traffic from mother to fetus.

Transmission characteristics of different students during a school outbreak of (H1N1) pdm09 influenza in China, 2009.

Many outbreaks of A(H1N1)pdm09 influenza have occurred in schools with a high population density. Containment of school outbreaks is predicted to help mitigate pandemic influenza. Understanding disease transmission characteristics within the school setting is critical to implementing effective control measures. Based on a school outbreak survey, we found almost all (93.7%) disease transmission occurred within a single grade, only 6.3% crossed grades. Transmissions originating from freshmen exhibited a star-shaped network; other grades exhibited branch- or line-shaped networks, indicating freshmen have higher activity and are more likely to cause infection. R0 for freshmen, calculated as 2.04, estimated as 2.76, was greater than for other grades (P < 0.01). Without intervention, the estimated number of cases was much greater when the outbreak was initiated by freshmen than by other grades. Furthermore, the estimated number of cases required to be under quarantine and isolation for freshmen was less than that of equivalent other grades. So we concluded that different grades have different transmission mode. Freshmen were the main facilitators of the spread of A(H1N1)pdm09 influenza during this school outbreak, so control measures (e.g. close contact isolation) priority used for freshmen would likely have effectively reduced spread of influenza in school settings.

[Construction and expression of a eukaryotic expression vector containing human CR2-Fc fusion protein].

OBJECTIVE: To construct a eukaryotic expression vector containing human complement receptor 2 (CR2)-Fc and express the CR2-Fc fusion protein in Chinese hamster ovary (CHO) cells. METHODS: The extracellular domain of human CR2 and IgG1 Fc were respectively amplified, ligated and inserted into the eukaryotic expression vector PCI-neo. After verified by restriction enzyme digestion and sequencing, the recombinant plasmid was transfected into CHO K1 cells. The ones with stable expression of the fusion protein were obtained by means of G418 selection. The expression of the CR2-Fc fusion protein was detected and confirmed by SDS-PAGE and Western blotting. RESULTS: Restriction enzyme digestion and sequencing demonstrated that the recombinant plasmid was valid. SDS-PAGE showed that relative molecular mass (Mr;) of the purified product was consistent with the expected value. Western blotting further proved the single band at the same position. CONCLUSION: We constructed the eukaryotic expression vector of CR2-Fc/PCI-neo successfully. The obtained fusion protein was active and can be used for the further study of the role in HIV control.

An outbreak of Mycoplasma pneumoniae caused by a macrolide-resistant isolate in a nursery school in China.

Eighteen out of 45 children were reported to have a respiratory illness during an outbreak at a temporary dormitory in a nursery school in China in 2011. To study the outbreak and to determine the risk factors for infection, an epidemiological investigation was performed. A standardized questionnaire was completed for a total of 45 children with the help of their guardians and parents. In addition, acute- and convalescent-phase serum samples and throat swabs from the children were taken for laboratory diagnosis. The diagnosis of a Mycoplasma-like illness was based on the following clinical criteria. The criteria were onset of illness after 31 May 2011, characterized by a cough, fever(>37.5 °C), or at least 3 of the following symptoms: fever, sore throat, cough or expectoration, and runny or stuffy nose. PCR-restriction fragment length polymorphism (PCR-RFLP), determination of MICs, and sequencing were performed to determine the genotype, antibiotic resistance, and sequence polymorphisms of the isolated strains, respectively. The paired sera revealed that 15 patients were infected with Mycoplasma pneumoniae. Epidemiology confirmed that this was a point source outbreak, characterized by a short incubation period, a high secondary attack rate, and a long period of hospitalization. PCR-RFLP analysis revealed that the 12 isolated strains of M. pneumoniae shared the same subtype P1 gene, and 23S rRNA sequence analysis showed that these strains harbored two macrolide-resistant gene-related point mutations at position 2063 and 2617. In this outbreak, the major risk factor was the distance between the bed of the first patient and the beds of close contacts (beds less than three meters apart). The strains isolated in this study were found to harbor two point mutations conferring macrolide resistance, indicating the importance of pathogen and drug resistance surveillance systems.

A novel trifunctional IgG-like bispecific antibody to inhibit HIV-1 infection and enhance lysis of HIV by targeting activation of complement.

BACKGROUND: The complement system is not only a key component of innate immunity but also provides a first line of defense against invading pathogens, especially for viral pathogens. Human immunodeficiency virus (HIV), however, possesses several mechanisms to evade complement-mediated lysis (CoML) and exploit the complement system to enhance viral infectivity. Responsible for this intrinsic resistance against complement-mediated virolysis are complement regulatory membrane proteins derived from the host cell that inherently downregulates complement activation at several stages of the cascade. In addition, HIV is protected from complement-mediated lysis by binding soluble factor H (fH) through the viral envelope proteins, gp120 and gp41. Whereas inhibition of complement activity is the desired outcome in the vast majority of therapeutic approaches, there is a broader potential for complement-mediated inhibition of HIV by complement local stimulation. PRESENTATION OF THE HYPOTHESIS: Our previous studies have proven that the complement-mediated antibody-dependent enhancement of HIV infection is mediated by the association of complement receptor type 2 bound to the C3 fragment and deposited on the surface of HIV virions. Thus, we hypothesize that another new activator of complement, consisting of two dsFv (against gp120 and against C3d respectively) linked to a complement-activating human IgG1 Fc domain ((anti-gp120 x anti-C3d)-Fc), can not only target and amplify complement activation on HIV virions for enhancing the efficiency of HIV lysis, but also reduce the infectivity of HIV through blocking the gp120 and C3d on the surface of HIV. TESTING THE HYPOTHESIS: Our hypothesis was tested using cell-free HIV-1 virions cultivated in vitro and assessment of virus opsonization was performed by incubating appropriate dilutions of virus with medium containing normal human serum and purified (anti-gp120 x anti-C3d)-Fc proteins. As a control group, viruses were incubated with normal human serum under the same conditions. Virus neutralization assays were used to estimate the degree of (anti-gp120 x anti-C3d)-Fc lysis of HIV compared to untreated virus. IMPLICATIONS OF THE HYPOTHESIS: The targeted complement activator, (anti-gp120 x anti-C3d)-Fc, can be used as a novel approach to HIV therapy by abrogating the complement-enhanced HIV infection of cells.

Multilocus outbreak of foodborne botulism linked to contaminated sausage in Hebei province, China.

In 2007, an outbreak of foodborne botulism occurred in Hebei province, China. An epidemiological investigation and laboratory detection studies showed that sausage contaminated by type A Clostridium botulinum caused this outbreak of food poisoning. Its clinical and epidemiological features were different from previous reports of food poisoning.

A new therapeutic strategy for lung tissue injury induced by influenza with CR2 targeting complement inhibitor.

BACKGROUND: Influenza is a respiratory disease that seriously threatens human health. In fact, influenza virus itself does not make critical contribution to mortality induced by influenza, but "cytokine storm" produced by the excessive immune response triggered by the virus can result in inflammatory reaction of lung tissues and fatal lung tissue injury, and thus increase influenza mortality. Therefore, besides antiviral drugs, immunosuppression drugs should also be included in infection treatment. PRESENTATION OF THE HYPOTHESIS: Complement is the center of inflammatory reaction. If complement system is over activated, the body will have strong inflammatory reaction or tissue injury, resulting in pathological process. Many studies have proved that, inflammatory injury of lung tissues caused by influenza virus is closely related to complement activation. Therefore, inhibiting complement activation can significantly reduce inflammatory injury in lung tissues. As complement is both a physiological defense and pathological damage medium, systematic inhibition may result in side effects including infection. Therefore, we design targeting complement inhibitors for complement activation sites, i.e. with CR2 as targeting vector, complement inhibitors like CD59 and Crry are targeted to inflammatory sites to specially inhibit the complement activation in local injury, thus local inflammatory reaction is inhibited. TESTING THE HYPOTHESIS: CR2-CD59 and CR2-Crry targeting complement inhibitors are fusion-expressed, and their biological activity is examined via in vivo and in vitro tests. CR2 targeting complement inhibitors are used to treat mouse influenza viral pneumonia model, with PBS treatment group as the control. The survival and lung tissue injury of the mice is observed and the effect of CR2 targeting complement inhibitors on pneumonia induced by influenza virus is evaluated. IMPLICATIONS OF THE HYPOTHESIS: CR2 targeting complement inhibitors are expected to be ideal drugs for viral pneumonia.

A novel approach to inhibit HIV-1 infection and enhance lysis of HIV by a targeted activator of complement.

BACKGROUND: The complement system is one of the most potent weapons of innate immunity. It is not only a mechanism for direct protection against invading pathogens but it also interacts with the adaptive immunity to optimize the pathogen-specific humoral and cellular defense cascades in the body. Complement-mediated lysis of HIV is inefficient but the presence of HIV particles results in complement activation by the generation of many C3-fragments, such as C3dg and C3d. It has been demonstrated that activation of complement can enhance HIV infection through the binding of special complement receptor type 2 expression on the surface of mature B cells and follicular dendritic cells. PRESENTATION OF THE HYPOTHESIS: Previous studies have proven that the complement-mediated antibody-dependent enhancement of HIV infection is mediated by the association of complement receptor type 2 bound to the C3 fragment and deposited on the surface of HIV virions. Thus, we hypothesize that a new activator of complement, consisting of a target domain (C3-binding region of complement receptor type 2) linked to a complement-activating human IgG1 Fc domain (CR2-Fc), can target and amplify complement deposition on HIV virions and enhance the efficiency of HIV lysis. TESTING THE HYPOTHESIS: Our hypothesis was tested using cell-free HIV-1 virions cultivated in vitro and assessment of virus opsonization was performed by incubating appropriate dilutions of virus with medium containing normal human serum and purified CR2-Fc proteins. As a control group, viruses were incubated with normal human serum under the same conditions. Virus neutralization assays were used to estimate the degree of CR2-Fc-enhanced lysis of HIV compared to untreated virus. IMPLICATIONS OF THE HYPOTHESIS: The targeted complement activator, CR2-Fc, can be used as a novel approach to HIV therapy by abrogating the complement-enhanced HIV infection of cells.

HCV antibody response and genotype distribution in different areas and races of China.

Hepatitis C virus (HCV) heterogeneity accounts for the failure of effective vaccine development and the lack of successful anti-viral therapy in some patients. Little is known about the immune response to HCV peptides and the region or race specific genotypes in China. The objective of this study was to characterize HCV antibody immune response to HCV peptides and HCV genotypes in different regions and races of China. A total of 363 serum samples were collected from HCV carriers in 6 regions in China. The immune response to HCV peptides was evaluated by ELISA. HCV genotypes were examined using nested RT-PCR. We found that the anti-HCV antibody neutralization rates were significantly different among the serum samples from different areas or from different races in the same area. For samples from Tibet and Sinkiang, the rates of neutralization by HCV peptides were only 3.2% and 30.8%, respectively. The genotypes of samples from Tibet and Sinkiang were apparently heterogeneic and included type I, II, III and multiple types (I/II/III, I/II, I/III, II/III). One specific sample with multiple-genotype (I/II/III) HCV infection was found to consist of type I, II, III, II/III and an unclassified genotype. These studies indicate that the anti-HCV antibody immune response to HCV peptides varied across regions and among races. The distribution of HCV genotypes among Tibetans in Tibet and Uighurs in Sinkiang was different from that in the inner areas of China. In addition, a "master" genotype, type II, was found to exist in HCV infection with multiple HCV genotypes.