试论抗艾滋病治疗后的免疫重建

艾滋病 (AIDS)自 1998年以来在发达国家有了大转折 ,经过高效抗逆转录病毒治疗 (HAART)后 ,人类免疫缺陷病毒(HIV)自感染至发病和 AIDS的死亡率下降了 80 % ,很多发达国家的艾滋病疫情大有缓解 ,中国香港、韩国、新加坡等地的艾滋病得到遏制 ;发展中国家的多数因无力承担每例每     

单核细胞趋化蛋白-1在艾滋病合并肺结核中的研究进展

肺结核是威胁人类健康的重要疾病之一,随着艾滋病（AIDS）在世界范围内的流行,肺结核的发病率有增加的趋势,肺结核已成为AIDS患者主要的机会感染及死亡原因。在AIDS合并肺结核患者（双重感染者）中,人类免疫缺陷病毒-1（HIV-1）感染加剧了结核的播散。同时,结核分枝杆菌可促进HIV-1复制变异,最终导致病情进展恶化。研究发现：单核细胞趋化蛋白-1（MCP-1）在单纯肺结核患者中有较高表达,且与结核病情进展程度密切相关。而在AIDS合并肺结核患者中同样有高表达,两者存在显著性差异,提示MCP-1表达异常可能与AIDS合并肺结核患者病情进展恶化有关。     

艾滋病的免疫功能重建研究进展

人类免疫缺陷病毒(HIV)感染人体后主要引起CL4~+ T细胞进行性减少,细胞免疫功能缺陷,最后导致严重的机会性感染或肿瘤。1996年以前,人们一直认为艾滋病(AIDS)的免疫破坏是不可逆转的。高效联合抗逆转录病毒治疗(HAART)出现后,人们普遍接受了免疫能重建的观点,越来越多的研究表明HAART治疗后HIV/AIDS患者的免疫力可以恢复,并能够对抗机会性感染。随着对AIDS发病机制和免疫病理的深入研究,一些新的治疗策略和手段纷纷涌现,其目标在于更快和更进一步的恢复机体免疫力,以预防机会性感染和增加HIV特异性免疫力。本文对近年艾滋病免疫重建研究的一些新治疗策略进行如下简述。 1 CD4~+细胞减少的机制和免疫重建艾滋病的最主要免疫病理是CD4~+ T细胞数量的减少。感染HIV后体内CD4~+ T细胞数量不断减少,这种减少一般分4期。第1期以CD4~+ T细胞数量短期内一过性迅速减少     

人类免疫缺陷病毒免疫逃避机制研究进展

目前，人类免疫缺陷病毒(HIV)感染仍在世界范围内尤其在发展中国家呈上升趋势，在借鉴以往病毒防治经验的基础上，科学家们已经研制出了包括亚单位疫苗、减毒活疫苗、灭活疫苗、活载体疫苗、核酸疫苗、多成分联合疫苗，融合态疫苗等多种形式的防治性抗获得性免疫缺陷综合征(AIDS)疫苗，虽然有些类型的疫苗可以诱导出病毒特异性的体液及细胞免疫应答并已经进入Ⅰ期或Ⅱ期临床实验，     

艾滋病的免疫治疗

近来研发的抗艾滋病病毒(HIV)的新药有效地抑制了病毒的复制,部分患者机体免疫功能彻底恢复,症状缓解,存活时间延长。然而抗HIV-1化疗药物也有其缺陷,如产生药物毒性,出现耐药病毒株,部分患者治疗后无法完全抑制病毒复制。因此限制了药物的临床应用和实际效果。免疫治疗越来越受到人们的关注,治疗手段更多,艾滋病病人在治疗中获益良多。     

HIV-1亚型多样性及其对艾滋病防治影响的研究进展

人类免疫缺陷病毒1型(HIV-1)具有高度变异的特性。HIV-1有9种亚型和78种流行重组型,HIV-1亚型在全球呈不均匀分布。HIV-1亚型多样性可对病毒的传播途径和传播能力、毒力和疾病进展、药物敏感性和耐药性、疫苗研发产生影响,使艾滋病的防治形势面临着严峻的挑战。该文对其研究近况作一综述。     

艾滋病患者隐球菌性脑膜炎相关免疫重建炎症综合征的研究进展

免疫重建炎症综合征是艾滋病患者在接受抗反转录病毒治疗(anti-retroviral therapy, ART)后,血浆人类免疫缺陷病毒RNA载量下降,CD4 +T淋巴细胞计数升高,机体免疫功能恢复,但是其临床症状恶化甚至导致死亡的一种现象。10%～50%的艾滋病合并隐球菌性脑膜炎患者在ART过程中会出现隐球...     

医学生艾滋病健康教育模式的研究进展

艾滋病疫情感染人群年轻化,预防和控制艾滋病的重要基础工作在于学校预防艾滋病健康教育。医学生既是艾滋病健康教育对象,也将是宣传预防艾滋病相关知识的生力军,该文从对医学生实施艾滋病健康教育的必要性、模式、干预效果等方面进行综述。     

HIV-1耐药突变的研究进展

至2015年止,全球约有1 700万HIV/AIDS病例得到抗逆转录病毒治疗,使HIV-1死亡率和发病率迅速下降。随着抗逆转录病毒治疗向所有感染HIV者全面推进,HIV耐药突变问题对长期治疗也构成了威胁,并对全球2030年消除艾滋病这一重要公共卫生战略产生了负面影响。本综述试图从不同的经济和地理环境出发,从个体和群体水平上阐述了常用的抗逆转录病毒药物的遗传屏障、交互耐药程度、耐药突变的流行病学和耐药管理;同时本文汇总了高、中低两类国家的可传播性耐药(TDR)和获得性耐药(ADR)的流行方式,分析了两类具有重要的公共卫生意义HIV耐药突变问题,即治疗前耐药和暴露前预防性服药的耐药。此外,鉴于有效地对不同类国家的HIV病例的治疗和管理,分别分析了基因型耐药性检测和治疗实践方面的关联,这些内容对我国的艾滋病防治也具有一定的参考作用。     

HIV整合酶抑制剂的应用及耐药研究进展

目的艾滋病病毒(HIV)整合酶是病毒复制所必需的基本酶之一。它能够催化病毒复制周期中的整合过程,将病毒的cDNA整合入宿主基因组中。以雷替格韦(Raltegravir,RAL)为代表的整合酶抑制剂,是新一代治疗艾滋病的药物。随着其在临床上的应用,也不可避免地出现了耐药问题。文章综述了目前HIV整合酶抑制剂在临床上的应用以及耐药情况的最新进展。     

CD38 expression on CD8 T cells has a weak association with CD4 T-cell recovery and is a poor marker of viral replication in HIV-1-infected patients on antiretroviral therapy

OBJECTIVE: The aim of the study was to determine whether the expression of CD38 on CD8 T cells can identify patients with virological failure on antiretroviral therapy (ART). DESIGN: This was a cross-sectional study of patients attending a single HIV clinic in London. METHODS: The expression of CD38 on CD8 T cells was assessed using a biologically calibrated flow cytometry protocol. Patients were characterized by lymphocyte subset and viral load measurements. Characteristics including historical CD4 T cell counts, therapeutic history, co-infections and demographics were obtained from medical records. RESULTS: Elevated levels of CD8 CD38(high) T cells were found in HIV-1-infected patients who failed to suppress viral replication with ART; however, this parameter lacked sufficient sensitivity and specificity to replace viral load testing in assessing the efficacy of ART. Increased levels of CD8 CD38(high) cells were associated with reduced CD4 T cell counts in HIV-1-infected patients on ART after correcting for known determinants of CD4 T-cell recovery. CONCLUSIONS: The expression of CD38 on CD8 T cells lacks sufficient sensitivity and specificity to be used as a surrogate marker for viral load to monitor HIV-1 infection. T-cell activation is associated with reduced CD4 T-cell reconstitution in patients receiving ART.     

HIV-1与趋化因子受体的研究进展

近年来，HIV-1在借助趋化因子受体（CCR5，CXCR4）感染免疫细胞方面的研究引起了广泛关注。对趋化因子受体在HIV-1感染中结构与功能的研究对于促进人们了解艾滋病的发病机制及其预防具有重要意义。另外，对CCR5与CXCR4相关抑制剂的作用分析更为艾滋病疫苗的研制与应用提供了新的方向。本文就HIV-1与趋化因子受体的研究进展情况作一综述。     

深圳地区艾滋病患者HIV-1毒株膜蛋白V3环的氨基酸变异分析

目的了解深圳地区艾滋病患者体内不同HIV-1亚型膜蛋白V3环的氨基酸序列特征及变异特点.方法采用逆转录套式聚合酶链反应（RT-nested-PCR）对艾滋病患者血浆HIV RNA进行扩增,对扩增产物直接测序并进行序列对比、翻译和分析.结果深圳地区艾滋病患者感染HIV病毒分属B与CRF01-AE亚型,病毒V3顶端的四肽特征主要为：GPGQ 48%、GPGR 36%、其他形式16%;其中AE亚型GPGQ百分比为76.9%,B亚型GPGR百分比为75%;还发现DQDR、DQGQ等少见V3环顶端四肽组成形式.V3环发生与SI表型有关的氨基酸突变形式高达80%.结论深圳地区艾滋病患者感染病毒V3环顶端四肽主要为GPGQ与GPGR,V3环序列高度变异,出现一些少见的V3环顶端四肽组成形式值得进一步研究.     

Change in Nutritional and Biochemical Status in People Living with HIV-1 on Antiretroviral Therapy

Antiretroviral therapy (ART) improves the quality of life of people living with HIV-1 (PLHIV) and reduces the mortality rate, but some individuals may develop metabolic abnormalities. This study evaluated changes in the nutritional status and biochemistry of PLHIV on antiretroviral therapy in a cohort that had not previously received ART and to follow up these individuals for 24 months after starting treatment. The initial cohort consisted of 110 individuals and ended with 42 people, assessed by a physical examination. A biochemical assay was performed using the colorimetric enzyme reaction technique, the proviral load was detected by qPCR and the quantification of the CD4/CD8 T lymphocytes was conducted by flow cytometry. PLHIV had increased levels of total cholesterol, LDL, triglycerides, ALT, urea and creatinine after 24 months of ART use (p < 0.05). In the assessment of the nutritional status, PLHIV had increased measures of Triciptal Skinfold, body mass index and arm circumference after the use of ART (p < 0.05). The viral load levels decreased and the CD4 levels increased after 24 months of ART use (p < 0.05). The change in the nutritional status in PLHIV on antiretroviral therapy seems to be a slow process, occurring in the long term, therefore, there is the need for a constant evaluation of these people to identify patients who need a nutritional intervention.     

Replicative fitness of transmitted HIV-1 drives acute immune activation,proviral load in memory CD4+ T cells,and disease progression

HIV-1 infection is characterized by varying degrees of chronic immune activation and disruption of T-cell homeostasis, which impact the rate of disease progression. A deeper understanding of the factors that influence HIV-1–induced immunopathology and subsequent CD4⁺ T-cell decline is critical to strategies aimed at controlling or eliminating the virus. In an analysis of 127 acutely infected Zambians, we demonstrate a dramatic and early impact of viral replicative capacity (vRC) on HIV-1 immunopathogenesis that is independent of viral load (VL). Individuals infected with high-RC viruses exhibit a distinct inflammatory cytokine profile as well as significantly elevated T-cell activation, proliferation, and CD8⁺ T-cell exhaustion, during the earliest months of infection. Moreover, the vRC of the transmitted virus is positively correlated with the magnitude of viral burden in naive and central memory CD4⁺ T-cell populations, raising the possibility that transmitted viral phenotypes may influence the size of the initial latent viral reservoir. Taken together, these findings support an unprecedented role for the replicative fitness of the founder virus, independent of host protective genes and VL, in influencing multiple facets of HIV-1–related immunopathology, and that a greater focus on this parameter could provide novel approaches to clinical interventions.From the start of the AIDS epidemic, HIV-1 infection has been characterized by a steady decline in CD4⁺ T cells that results in a state of overt immunodeficiency marked by an increased susceptibility to opportunistic infections and malignancies (1). Although a majority of HIV-1–infected individuals eventually progress to AIDS during their lifetime, they do so at drastically different rates (2). Several immunological abnormalities during HIV-1 infection have been identified that correlate with disease progression, such as a rapid and robust expression of proinflammatory cytokines, chronic immune activation, cellular exhaustion, and infection of vulnerable memory CD4⁺ T-cell subsets important for maintaining T-cell homeostasis (3). The degree to which these pathogenic mechanisms are triggered early in infection may explain the varying rates of disease progression among individuals.It has been shown that the magnitude of immune activation during HIV-1 infection is established early, is relatively stable over time, and predicts the rate of disease progression better than viral load (4, 5). Successful antiretroviral treatment (ART) of HIV-1–infected individuals reduces viremia to undetectable levels, restores CD4⁺ T-cell counts to some degree, and significantly prolongs life (6). Despite this, ART does not fully restore immune function, and levels of residual immune activation are associated with an increased risk of morbidity and mortality (7, 8). Moreover, even with successful ART, the virus is not fully eradicated and viral rebound occurs upon treatment interruption (9). Strategies aimed at mitigating persistent immune activation and eradicating the latent viral reservoir will contribute immensely toward improving the quality of life of HIV-1–infected individuals and will help to curb the epidemic. Thus, a better understanding of the mechanisms driving HIV-1–induced immunological abnormalities and the processes by which they ultimately cause disease is crucial for unveiling novel avenues for pursuing these more advanced therapeutic interventions.To date, research has primarily focused on identifying host factors that contribute to viral control and favorable disease outcomes, whereas viral characteristics have received less scrutiny (10, 11). HLA class I alleles such as HLA-B*57 and B*5801 have been shown to influence viral load and CD4⁺ T-cell decline through the induction of a strong CD8⁺ T-cell response that is able to target functionally vulnerable regions of the genome such as the structural protein Gag (10). The observation that not all individuals harboring such protective HLA class I alleles go on to become long-term nonprogressors suggests that other factors outside of host immunogenetics play a role in defining disease progression (12). Transmitted viral characteristics have been shown to impact viral load within heterosexual transmission pairs, suggesting that viral characteristics are heritable and can impact disease severity (11, 13, 14). Moreover, we recently showed that attenuated viral replicative capacity (vRC) of the transmitted virus, defined in vitro by the Gag sequence, was associated with a significant delay in CD4⁺ T-cell decline in individuals recently infected with HIV-1 subtype C (15). Because this clinical benefit appeared to be partially independent of set point viral load (SPVL), we hypothesized that high levels of transmitted/founder virus replication might initiate irreversible pathogenic events early in infection. Specifically, we hypothesized that high vRC might lead to exacerbated immune activation, elevated cellular dysfunction, and increased infection of memory CD4⁺ T-cell subsets, which in total might dictate the kinetics of subsequent disease progression (15).To test this hypothesis, we have studied a unique cohort of 127 Zambian seroconvertors acutely infected (median 46 d postinfection) with HIV-1 subtype C that have up to 6 y of longitudinal follow-up. We show here that transmission of high-vRC HIV-1 is associated with a distinct inflammatory profile marked by significantly higher levels of proinflammatory cytokines, increased cellular immune activation and exhaustion, and higher levels of proviral burden in naive and central memory CD4⁺ T-cell subsets at early time points after infection. Thus, the replicative capacity of transmitted HIV-1, defined by the structural protein Gag, is a critical factor in defining early immune activation, the preservation or loss of CD4⁺ T-cell homeostasis, and the subsequent trajectory of disease progression. Interventions including early antiretroviral therapy or vaccine-induced immunity that impact these early events and that attenuate early viral replication will have a significant effect on the development of clinical disease.     

Assessment of mother-to-child HIV-1 and HIV-2 transmission: an AIDS reference laboratory collaborative study

Objective

A prospective study was carried out to assess HIV‐1 and HIV‐2 mother‐to‐child transmission (MTCT) rates in Portugal between 1999 and 2005 by analysing the proportion of diagnosed infected children born to HIV‐positive mothers.

Materials and methods

Serial blood samples were collected from 1315 children at risk of HIV‐1 infection, 131 children at risk of HIV‐2 infection and six children at risk of both HIV‐1 and HIV‐2 infections attending 25 Health Institutions. HIV proviral DNA was detected by nested polymerase chain reaction (PCR) and statistical analysis was performed using spss .

Results

DNA PCR using HIV‐1 and HIV‐2 long terminal repeat (LTR) primers amplified 92.5% and 75% of maternal HIV infections, respectively. Overall, MTCT occurred in 3.4% [95% confidence interval (CI) 2.5–4.6%] of HIV‐1 and 1.5% (95% CI 0.2–5.4%) of HIV‐2 mother–child pairs. A significant decrease in HIV‐1 MTCT was observed with time, from 7.0% (95% CI 2.6–14.6%) in 1999 to 0.5% (95% CI 0.0–2.5%) in 2005. HIV MTCT was associated with an absence of antiretroviral therapy in infected pregnant women (P<0.0001). Of the 48 infected children (46 with HIV‐1 and two with HIV‐2), the schedule of blood sample collection was followed for only 26 children. In 14 (53.8%) of those 26 children the infections were diagnosed in the first sample collected before they were 48 h old, suggesting in utero transmission. Despite the national recommendations for antenatal HIV testing, a high overall proportion (22.2% for HIV‐1 and 44.3% for HIV‐2) of mothers did not access any MTCT prevention measures, mostly because of late diagnosis in pregnancy. A small but significant proportion of HIV‐2 infection was found in mothers with no identifiable link with West Africa.

Conclusion

HIV‐2 transmission rates are low (1.5% in this study), and this may have led to a lower uptake of interventions, but in the absence of interventions transmission does occur. HIV‐1 transmission was also associated with a lack of intervention, mostly as a result of late presentation. Use of primers restricted to a single sequence led to false‐negative maternal results in a significant proportion of cases. In part this may have been attributable to very low HIV DNA loads as well as primer template mismatches. HIV infection was not documented in children born to mothers with negative HIV DNA PCR results.     

Proviral HIV-1 dynamics and evolution in patients receiving efficient long-term antiretroviral combination therapy

Different experimental approaches have shown that, despite plasma viral loads under the threshold of detection, HIV-1 frequently continues to replicate in patients receiving potent antiretroviral therapy. However, whether this low-grade viral replication is sufficient for the generation of new major quasispecies has not been studied. Thus, in order to evaluate the extent of variation in the major proviral HIV-1 population, we monitored proviral DNA sequences in such patients over a time period of up to 30 months.
Methods   DNA was extracted from peripheral blood mononuclear cells (PBMC) and the V3 region was amplified by nested polymerase chain reaction (PCR) and directly sequenced. Additionally, both HIV-1 RNA and DNA levels and CD4⁺ T-lymphocyte counts were monitored.
Results   Analysing the V3 gene sequences of 17 patients, we observed a sequence evolution in nine patients. Interestingly, the majority of these changes (77%) occurred in the first interval following the initiation of therapy and despite signs of ongoing replication the proviral DNA levels continued to decrease in all patients.
Conclusions   Our data suggest that, although available data report that HIV-1 continues to replicate in patients with undetectable viraemia, the extent of viral replication in many of these patients is not sufficient to result in changes in the major viral population.     

Impact of immune interventions on proviral HIV-1 DNA decay in patients receiving highly active antiretroviral therapy

Objective   To measure the evolution of proviral HIV-1 DNA levels in patients receiving highly active antiretroviral therapy (HAART) compared to those treated with HAART plus interleukin-2 (IL-2) and hydroxyurea.
Design   Prospective randomised trial.
Methods   Twenty-two HIV-1 infected patients were randomly assigned to a five-drug antiretroviral regimen for 72 weeks, with or without IL-2, followed by a three-drug regimen up to week 120 with additional hydroxyurea in patients having received IL-2. HIV-1 DNA levels in peripheral blood mononuclear cells (PBMC) were measured regularly using the Amplicor Monitor kit from Roche Diagnostics (Meylan, France). Potentially infectious HIV-1 was cultured in enhanced conditions from circulating CD4 T cells at week 120.
Results   During the study period of 120 weeks, HIV-1 DNA levels in PBMC decreased by −1.1 log in patients treated with HAART only compared with −1.8 log in patients with additional IL-2 and hydroxyurea. A two-phase decay rate was observed, with an inflexion point at 12 weeks. The second decay was slow, with mean half-lives of 130.1 ± 21.3 weeks and 95.1 ± 26.3 weeks for patients on HAART and those receiving additional IL-2 and hydroxyurea, respectively. At week 120, one out of 11 patients with HAART alone compared to six out of 11 in the group with IL-2 and hydroxyurea had undetectable proviral DNA levels and three of them had unsuccessful recovery of replication-competent HIV-1 from blood CD4 T cells.
Conclusion   Therapeutic strategies combining HAART and immune interventions have higher potency to decrease the number of infected cells than HAART alone.