Development and Challenge of HIV/AIDS Testing Laboratory Network and Quality Assurance System in China

This paper describes the development and challenge of HIV/AIDS testing laboratory network and quality assurance system in China. At present,the HIV/AIDS testing laboratories includes three classes,the National AIDS Reference Laboratory,HIV/AIDS confirmatory laboratories and HIV/AIDS screening laboratories. All of them are accredited by the health authorities,and each class of laboratories take charge of their function strictly according to the "National Management of HIV/AIDS Detection (2006)". A complete quality assurance and quality control system for HIV/AIDS testing has been developed,which includes technical training,strict laboratory monitoring and approval,examination or proficiency testing on HIV/AIDS detection,and quality evaluation and supervision of HIV/AIDS diagnostic kits. Besides conduct the routine anti-HIV antibody test,more and more laboratories began to conduct other tests,such as CD4 T lymphocyte cell counting,HIV viral load,HIV DNA PCR,genotyping,drug resistance,and HIV-1 recent infection test. The primary challenges faced by the HIV/AIDS testing laboratory network are in the areas of laboratory management and quality control. For example,the provincial PT program is inefficient,the internal quality control is conducted perfunctorily,personnel training can not met the needs of the workplace,which need to be improved.     

On transient effects in the HIV/AIDS epidemic

During the initially exponential spread of the human immunodeficiency virus (HIV—the causative agent of AIDS) the growth rate of the number of AIDS cases decreases from plus infinity to the growth rate of HIV infections. A sensitivity analysis shows that for all reasonable values of the parameters of the HIV epidemic (incubation period, initial doubling time, etc.) the effect of this positive transient becomes negligible when the annual number of AIDS cases reaches a few dozen. Necessary and sufficient conditions are given for the growth rate of the number of AIDS cases to be monotonically decreasing during the positive transient. A mildly pathological density function for the incubation period of AIDS provides an example of a growth rate of AIDS that does not decrease monotonically, even though HIV is spreading exponentially. A negative transient occurs when the growth rate of HIV begins to decrease. In this context a somewhat surprising result emerges under the assumption that the growth rate of HIV is non-increasing: the growth rate of AIDS is at all times larger than the growth rate of HIV. A logistic HIV epidemic illustrates this result, and implications for the growth of the HIV epidemic in the United States and Europe are discussed. In particular, it is shown that the positive transient must have passed by 1982 in the United States and by 1986 or 1987 for the five European countries with the largest caseloads.     

Analysis of recruitment and industrial human resources management for optimal productivity in the presence of the HIV/AIDS epidemic

The aim of this paper is to analyze the recruitment effects of susceptible and infected individuals in order to assess the productivity of an organizational labor force in the presence of HIV/AIDS with preventive and HAART treatment measures in enhancing the workforce output. We consider constant controls as well as time-dependent controls. In the constant control case, we calculate the basic reproduction number and investigate the existence and stability of equilibria. The model is found to exhibit backward and Hopf bifurcations, implying that for the disease to be eradicated, the basic reproductive number must be below a critical value of less than one. We also investigate, by calculating sensitivity indices, the sensitivity of the basic reproductive number to the model’s parameters. In the time-dependent control case, we use Pontryagin’s maximum principle to derive necessary conditions for the optimal control of the disease. Finally, numerical simulations are performed to illustrate the analytical results. The cost-effectiveness analysis results show that optimal efforts on recruitment (HIV screening of applicants, etc.) is not the most cost-effective strategy to enhance productivity in the organizational labor force. Hence, to enhance employees’ productivity, effective education programs and strict adherence to preventive measures should be promoted.     

Evaluation of Epstein-Barr Virus Salivary Shedding in HIV/AIDS Patients and HAART Use: A Retrospective Cohort Study

Little data is available on the evaluation of the occurrence rates of Epstein-Barr virus(EBV) in saliva and relationship with highly active antiretroviral therapy(HAART) use in HIV/AIDS patients in China. We conducted a retrospective cohort study of EBV serological tests for HIV/AIDS patients who were treated in the hospitals for infectious diseases in Wuxi and Shanghai, China from May 2016 to April 2017. The EBV-seropositive samples were identified by ELISA. EBV-specific primers and probes were used for the quantitative detection of viral DNA from saliva via quantitative real-time polymerase chain reaction. CD4 cell counts of the HIV/AIDS patients were detected by a flow cytometry. A total of 372 HIV/AIDS patients were ultimately selected and categorized for this retrospective cohort study. For EBV IgG and IgM, the HIV/AIDS HAART use(H) and non-HAART use(NH) groups had significantly higher seropositive rates than the HIV-negative control group. The HIV/AIDS(NH) group had the highest seropositive rate(IgG, 94.27%; IgM, 68.98%) and the highest incidence of EBV reactivation or infection. For salivary EBV DNA-positive rates and quantities, the HIV/AIDS(H)(73.69%) and the HIV/AIDS(NH)(100%) groups showed significantly higher values than the HIV-negative control group(35.79%,[ twofold). Further, the salivary EBV DNA-negative population had significantly higher CD4 cell counts than the EBV DNA-positive population in the HIV/AIDS(H) group and the HIV/AIDS(NH) groups. Thus, HAART use is beneficial in decreasing the EBV salivary shedding in HIV/AIDS patients and indirectly decreases EBV transmission risk.     

Prevalence of HIV Indeterminate Western Blot Tests and Follow-up of HIV Antibody Sero-Conversion in Southeastern China

HIV-indeterminate Western blotting(WB) results are typically obtained in WB confirmatory assays, and the number of indeterminate samples may increase with the detection of HIV infections, which will present considerable challenges for the management of HIV/AIDS. Nucleic acid detection has been used as a laboratory test for screening suspected or indeterminate samples. However, the effectiveness of these assays for the differential diagnosis of HIV-indeterminate WB samples remained undetermined. In this study, 210 subjects with HIV-indeterminate WB results were detected from 6360 positive HIV screening samples between 2015 and 2016 in southeastern China, in which HIV-indeterminate WB results accounted for 3.30%. The highest proportion of indeterminate results was observed in pregnant and lying-in women receiving physical examinations(16.67%), followed by that in voluntary blood donors(8.82%). The most common WB band patterns were p24, gp160 and p24, and gp160. The follow-up study revealed that the highest negative and positive conversion rates of HIV antibodies were in samples with a single p24 band(80.28%), and with gp160 and p24 bands(86.21%), respectively. Among the Env, Gag, and Pol antibodies, samples with a Gag band showed the highest negative conversion rate(81.25%), whereas the highest positive conversion rate was observed in samples with an Env band(56.76%). In addition, quantitative and qualitative HIV nucleic acid testing exhibited the highest sensitivity(96.3%) and specificity(97.85%), respectively. Our results indicate a lower proportion of HIV indeterminate WB results in southeastern China compared to previous reports, and the follow-up re-examination of patients with HIV indeterminate results should be performed. Nucleic acid testing facilitates the identification of HIV infections.     

Implications of HIV specific cytotoxic T lymphocytes in AIDS

The immune response to HIV in infected humans leads to the production of HIV specific cytotoxic T lymphocytes (CTL) which circulate in high frequencies. The presence of these CTL and their eventual protective activities have been studied by various laboratories, and correlations have been made with certain immunopathological manifestations of HIV infections. It seems probable that HIV-immune CTL participate in the induction of certain disorders by initiating inflammatory reactions in the lungs, central nervous system, and lymph nodes. Various virus antigens recognized by HIV-immune CTL on the surface of the infected cell have been identified, and the molecular definition of the epitopes recognized is well under way. Likewise, numerous HLA transplantation antigens that regulate HIV antigen recognition by CTL have been identified. These data are discussed in view of the development of an eventual vaccine and of functional immunotherapies. They are compared with results obtained in animal experimental systems.Deceased     

HIV and HCV： from Co-infection to Epidemiology, Transmission, Pathogenesis, and Treatment

Human immunodeficiency virus (HIV) is the infectious agent causing acquired immu-nodeficiency syndrome (AIDS),a deadliest scourge of human society. Hepatitis C virus (HCV) is a major causative agent of chronic liver disease and infects an estimated 170 million people worldwide,resulting in a serious public health burden. Due to shared routes of transmission,co-infection with HIV and HCV has become common among individuals who had high risks of blood exposures. Among hemophiliacs the co-infection rate accounts for 85%; while among injection drug users (IDU) the rate can be as high as 90%. HIV can accelerate the progression of HCV-related liver disease,particularly when immunodeficiency has developed. Although the effect of HCV on HIV infection is controversial,most studies showed an increase in mortality due to liver disease. HCV may act as a direct cofactor to fasten the progression of AIDS and decrease the tolerance of highly active antiretroviral therapy (HARRT). Conversely,HAART-related hepatotoxicity may enhance the progression of liver fibrosis. Due to above complications,co-infection with HCV and HIV-1 has imposed a critical challenge in the management of these patients. In this review,we focus on the epidemiology and transmission of HIV and HCV,the impact of the two viruses on each other,and their treatment.     

HIV and HCV: from Co-infection to epidemiology, transmission, pathogenesis, and treatment

Human immunodeficiency virus (HIV) is the infectious agent causing acquired immunodeficiency syndrome (AIDS), a deadliest scourge of human society. Hepatitis C virus (HCV) is a major causative agent of chronic liver disease and infects an estimated 170 million people worldwide, resulting in a serious public health burden. Due to shared routes of transmission, co-infection with HIV and HCV has become common among individuals who had high risks of blood exposures. Among hemophiliacs the co-infection rate accounts for 85%; while among injection drug users (IDU) the rate can be as high as 90%. HIV can accelerate the progression of HCV-related liver disease, particularly when immunodeficiency has developed. Although the effect of HCV on HIV infection is controversial, most studies showed an increase in mortality due to liver disease. HCV may act as a direct cofactor to fasten the progression of AIDS and decrease the tolerance of highly active antiretroviral therapy (HARRT). Conversely, HAART-related hepatotoxicity may enhance the progression of liver fibrosis. Due to above complications, co-infection with HCV and HIV-1 has imposed a critical challenge in the management of these patients. In this review, we focus on the epidemiology and transmission of HIV and HCV, the impact of the two viruses on each other, and their treatment.      

A modeled time-varying density function for the incubation period of AIDS

Building on the Weibull distribution, we develop a modeled time-varying density function of the incubation time between exposure to HIV infection and full-blown AIDS. This approach leads to a series of cohort-specific density functions that take into account the increasing impact of new therapies such as zidovudine (AZT). The resulting modeled density functions are studied in detail, particularly with regard to their modes and medians. The mode is sensitive to changes in the period incubation time distribution, with even a possibility of a bimodal distribution for certain combinations of the parameters that determine the rate at which the period median incubation time changes. An important substantive result is that when a period median incubation period slowly increases to some leveling off value, say m(x _c ), then it is surprisingly early on that cohorts of infected individuals have a median incubation period very close to that ultimate value m(x _c ).     

On the role of long incubation periods in the dynamics of acquired immunodeficiency syndrome (AIDS)

In this study, we investigate systematically the role played by the reproductive number (the number of secondary infections generated by an infectious individual in a population of susceptibles) on single group populations models of the spread of HIV/AIDS. Our results for a single group model show that if R 1, the disease will die out, and strongly suggest that if R > 1 the disease will persist regardless of initial conditions. Our extensive (but incomplete) mathematical analysis and the numerical simulations of various research groups support the conclusion that the reproductive number R is a global bifurcation parameter. The bifurcation that takes place as R is varied is a transcritical bifurcation; in other words, when R crosses 1 there is a global transfer of stability from the infection-free state to the endemic equilibrium, and vice versa. These results do not depend on the distribution of times spent in the infectious categories (the survivorship functions). Furthermore, by keeping all the key statistics fixed, we can compare two extremes: exponential survivorship versus piecewise constant survivorship (individuals remain infectious for a fixed length of time). By choosing some realistic parameters we can see (at least in these cases) that the reproductive numbers corresponding to these two extreme cases do not differ significantly whenever the two distributions have the same mean. At any rate a formula is provided that allows us to estimate the role played by the survivorship function (and hence the incubation period) in the global dynamics of HIV. These results support the conclusion that single population models of this type are robust and hence are good building blocks for the construction of multiple group models. Our understanding of the dynamics of HIV in the context of mathematical models for multiple groups is critical to our understanding of the dynamics of HIV in a highly heterogeneous population.     

Rates of amino acid change in the envelope protein correlate with pathogenicity of primate lentiviruses

A spectrum of pathogenicity has been observed for primate lentiviruses in their natural hosts. For example, human immunodeficiency virus type 1 (HIV-1) is a potent etiologic agent for AIDS in man, whereas there is no evidence to date which indicates that simian immunodeficiency virus from African green monkeys (SIVAGM) causes immunodeficiency in AGM. We measured the relative rates of amino acid change, as the ratio of the number of nonsynonymous to synonymous (silent) nucleotide substitutions, for six primate lentiviruses evolving in their respective hosts. These rates for the external envelope glycoprotein (gp120) and gag coding sequences are 2–3 times higher for pathogenic HIV-1 and SIV..ac (macaque) than for minimally pathogenic SIVAGM and SIVsn,m (sooty mangabey), and intermediate for HIV-2. We speculate that the increased rates of nonsynonymous changes in gp120 and gag coding sequences are due to viral escape from immune surveillance and are indicative of higher immunogenicity of these proteins in their hosts. Based on these results and available experimental data, we conclude that there is a positive correlation between lentiviral pathogenicity and immunogenicity of the Env and Gag proteins in a given host. This hypothesis is consistent with recent data suggesting that immune system activation or autoimmunity induced by viral antigens may be important in the pathogenesis of AIDS.Correspondence to: E.G. Shpaer     

吸毒人群中HIV/HCV核酸和抗体关系的分析

研究了高危人群中HIV/HCV核酸和抗体的关系。从新疆地区采集吸毒人群的血样,并对其进行HIV/ HCV核酸和抗体的检测。320例吸毒人员血浆样品中HCV抗体阳性为80．3％,HIV抗体阳性率为41．9％,HIV 和HCV共感染者为38．3％。HIV RNA与抗体的总符合率为98．8%,在186例HIV抗体阴性样品中可能有2例 为HIV感染的窗口期。HCV抗体和HCV RNA的阳性符合率为92．6％,HCV RNA与HCV抗体的总符合率为 90．0％,以上结果说明在HIV／HCV的高流行区进行HIV／HCV核酸检测可以发现病毒感染的窗口期,而约8% 的HCV抗体阳性样品为病毒核酸阴性,也值得进一步研究。     

Synthesis and comparison of substituted 1,2,3-dithiazole and 1,2,3-thiaselenazole as inhibitors of the feline immunodeficiency virus (FIV) nucleocapsid protein as a model for HIV infection

We report the first biological evaluation the 1,2,3-thiaselenazole class of compound and utilising a concise synthetic approach of sulfur extrusion, selenium insertion of the 1,2,3-dithiazoles. We created a small diverse library of compounds to contrast the two ring systems. This approach has highlighted new structure activity relationship insights and lead to the development of sub-micro molar anti-viral compounds with reduced toxicity. The 1,2,3-thiaselenazole represents a new class of potential compounds for the treatment of FIV and HIV.     

替换HIV-1衣壳蛋白基因SHIV的构建及其活性测定

将猴免疫缺陷病毒(Simianimmunodeficiencyvirus,SIVmm239)中gag基因的衣壳蛋白部分置换成人免疫缺陷病毒(Humanimmunodeficiencyvirustype1,HIV-1HXBc2)的相应部分,构建出替换了衣壳蛋白基因的人/猿嵌合免疫缺陷病毒(SHIV)原病毒DNA。用此SHIV原病毒DNA转染293T细胞,细胞中能够检测到嵌合病毒基因的转录与翻译;在细胞培养液上清中亦可检测到装配出的病毒颗粒。病毒颗粒形态正常,含有基因组RNA,具有反转录酶活性,嵌合的外源衣壳蛋白能够正确剪切,形成棒状的核心。将此嵌合SHIV病毒感染MT4细胞,病毒能够吸附并进入细胞,能完成反转录过程,但不能增殖。     

The role of HIV replicative fitness in perinatal transmission of HIV

Perinatal transmission of Human immunodeficiency virus(HIV),also called mother-to-child transmission(MTCT),accounts for 90% of infections in infants worldwide and occurs in 30%-45% of children born to untreated HIV-1 infected mothers.Among HIV-1 infected mothers,some viruses are transmitted from mothers to their infants while others are not.The relationship between virologic properties and the pathogenesis caused by HIV-1 remains unclear.Previous studies have demonstrated that one obvious source of selective pressure in the perinatal transmission of HIV-1 is maternal neutralizing antibodies.Recent studies have shown that viruses which are successfully transmitted to the child have growth advantages over those not transmitted,when those two viruses are grown together.Furthermore,the higher fitness is determined by the gp120 protein of the virus envelope.This suggests that the selective transmission of viruses with higher fitness occurred exclusively,regardless of transmission routes.There are many factors contributing to the selective transmission and HIV replicative fitness is an important one that should not be neglected.This review summarizes current knowledge of the role of HIV replicative fitness in HIV MTCT transmission and the determinants of viral fitness upon MTCT.     

HIV(+)/AIDS并发肺结核与单纯肺结核患者临床对照分析

提高对HIV(+)/AIDS并发肺结核临床表现的认识。方法:选取1998年以来我院收治的HIV(+)/AIDS并发肺结核的病例共47例为观察组(A组),及同期住院的HIV(-)单纯肺结核病例50例为对照组(B组)进行回顾性对照分析。结果:(1)A组发烧和体重下降较B组更常见,而咳嗽和咯血较B组少见;(2)A组痰抗酸杆菌阳性率显著低于B组;(3)A组结核杆菌培养阳性率显著低于B组,而耐多药结核(MDR-TB)所占比率显著高于B组;(4)肺结核的X线表现为弥漫性浸润或粟粒性阴影的,A组多于B组,而A组影像学空洞率显著低于B组;(5)A组合并肺外结核较B组多见,A组淋巴系统较B组常发生结核病变,A组全身血液播散性结核病的发病率明显高于B组;(6)PPD结核菌素反应阳性率A组显著低于B组,A组PPD阳性率与外周CD4+T淋巴细胞数相关。结论:HIV(+)/AIDS患者并发肺结核临床表现不典型。     

The Role of HIV Replicative Fitness in Perinatal Transmission of HIV

Perinatal transmission of Human immunodeficiency virus(HIV),also called mother-to-child transmission(MTCT),accounts for 90% of infections in infants worldwide and occurs in 30%-45% of children born to untreated HIV-1 infected mothers.Among HIV-1 infected mothers,some viruses are transmitted from mothers to their infants while others are not.The relationship between virologic properties and the pathogenesis caused by HIV-1 remains unclear.Previous studies have demonstrated that one obvious source of selectiv...     

HIV vaccine development in the nonhuman primate model of AIDS

Development of a prophylactic human immunodeficiency virus type 1 (HIV-1) vaccine is a leading priority in biomedical research. Much of this work has been done with the nonhuman primate model of AIDS. In a historical context, vaccine studies, which use this model, are summarized and discussed.     

＂Unconventional＂ Neutralizing Activity of Antibodies Against HIV

Neutralizing antibodies are recognized to be one of the essential elements of the adaptive immune response that must be induced by an effective vaccine against HIV. However,only a limited number of antibodies have been identified to neutralize a broad range of primary isolates of HIV-1 and attempts to induce such antibodies by immunization were unsuccessful. The difficulties to generate such antibodies are mainly due to intrinsic properties of HIV-1 envelope spikes,such as high sequence diversity,heavy glycosylation,and inducible and transient nature of certain epitopes. In vitro neutralizing antibodies are identified using "conventional" neutralization assay which uses phytohe-magglutinin (PHA)-stimulated human PBMCs as target cells. Thus,in essence the assay evaluates HIV-1 replication in CD4 T cells. Recently,several laboratories including us demonstrated that some monoclonal antibodies and HIV-1-specific polyclonal IgG purified from patient sera,although they do not have neutralizing activity when tested by the "conventional" neutralization assay,do exhibit potent and broad neutralizing activity in "unconventional" ways. The neutralizing activity of these antibodies and IgG fractions is acquired through post-translational modifications,through opsonization of virus particles into macrophages and immature dendritic cells (iDCs),or through expression of antibodies on the surface of HIV-1-susceptible cells. This review will focus on recent findings of this area and point out their potential applications in the development of preventive strategies against HIV.     

“Unconventional” neutralizing activity of antibodies against HIV

Neutralizing antibodies are recognized to be one of the essential elements of the adaptive immune response that must be induced by an effective vaccine against HIV. However, only a limited number of antibodies have been identified to neutralize a broad range of primary isolates of HIV-1 and attempts to induce such antibodies by immunization were unsuccessful. The difficulties to generate such antibodies are mainly due to intrinsic properties of HIV-1 envelope spikes, such as high sequence diversity, heavy glycosylation, and inducible and transient nature of certain epitopes. In vitro neutralizing antibodies are identified using “conventional” neutralization assay which uses phytohe-magglutinin (PHA)-stimulated human PBMCs as target cells. Thus, in essence the assay evaluates HIV-1 replication in CD4⁺ T cells. Recently, several laboratories including us demonstrated that some monoclonal antibodies and HIV-1-specific polyclonal IgG purified from patient sera, although they do not have neutralizing activity when tested by the “conventional” neutralization assay, do exhibit potent and broad neutralizing activity in “unconventional” ways. The neutralizing activity of these antibodies and IgG fractions is acquired through post-translational modifications, through opsonization of virus particles into macrophages and immature dendritic cells (iDCs), or through expression of antibodies on the surface of HIV-1-susceptible cells. This review will focus on recent findings of this area and point out their potential applications in the development of preventive strategies against HIV. Foundation item: Chinese Ministry of Science and Technology 973 program grant awarded to Paul Zhou (2006CB504308).