HIV/AIDS患者机会性感染与CD4+ T淋巴细胞间的关联性

目的 研究人免疫缺陷病毒（HIV）感染者及艾滋病（AIDS）患者发生机会性感染的概率与自身CD4+ T淋巴细胞之间的关系,为HIV患者机会性感染的防治提供参考。方法 以2016年6月至2017年6月我院400例HIV患者为研究对象,回顾性分析不同CD4+T淋巴细胞计数HIV患者发生机会性感染的情况。结果 400例HIV患者发生机会性感染178例,总感染率为44.5%。CD4+T淋巴细胞计数≤50个/μL的患者机会性感染发生率（86.67%）最高,与其他各组比较差异有统计学意义（P<0.05）。随着CD4+ T淋巴细胞计数的减少,HIV患者机会性感染率升高。178例机会性感染者中,单一感染82例,2部位感染52例,3部位感染28例,4部位以上感染16例。感染病原体检测显示,细菌感染84例（47.19%）,结核杆菌感染36例（20.22%）,病毒感染30例（16.85%,包括巨细胞病毒感染18例、单纯疱疹病毒感染12例）,真菌感染77例（43.25%,包括假丝酵母感染35例,肺孢子菌感染20例,马尔尼菲青霉菌感染12例,新型隐球菌感染10例）,未明确病原体性质34例（19.10%）,复合感染多见。结论 CD4+ T淋巴细胞水平与HIV患者继发机会性感染的概率关系密切。HIV患者CD4+ T淋巴细胞水平的监测对其继发机会性感染的防控具有重要临床意义。     

Epidemiology of Invasive Fungal Infections in Patients with Acquired Immunodeficiency Syndrome at a Reference Hospital for Infectious Diseases in Brazil

Invasive fungal infections (IFIs) represent one of the main causes of morbimortality in immunocompromised patients. Pneumocystosis, cryptococcosis and histoplasmosis are the most frequently occurring IFIs in patients with acquired immunodeficiency syndrome (AIDS). Fungi, such as Candida spp. and Aspergillus spp., may cause severe diseases during the course of an HIV infection. Following the introduction of highly active anti-retroviral therapy, there has been a marked reduction of opportunistic fungal infections, which today is 20–25 % of the number of infections observed in the mid-1990s. This study is an observational and retrospective study aimed at the characterising IFI incidence and describing the epidemiology, clinical diagnostic and therapeutic features and denouement in HIV/AIDS patients. In HIV/AIDS patients, the IFI incidence is 54.3/1,000 hospitalisation/year, with a lethality of 37.7 %. Cryptococcosis represents the main opportunistic IFI in the population, followed by histoplasmosis. Nosocomial pathogenic yeast infections are caused principally by Candida spp., with a higher candidemia incidence at our institution compared to other Brazilian centres.     

Serum thymidine kinase (TK) evaluation in HIV infection

Serum thymidine kinase (TK), measured using Prolifigen TK-REA, from AB Sangtec Medical, was investigated in 24 HIV seropositive patients without immunological alterations, 26 seropositives with immunological alterations, 125 LAS, 25 ARC, and 20 AIDS. Subjects with serological markers of prior EBV, HBV, and CMV infection were included but none with acute infectious mononucleosis or acute viral hepatitis. Serum TK was elevated from the beginning of the HIV infection, the seropositive stage, and more markedly afterwards during the course of the infection, with a close correlation with the stage. TK also increased during AZT treatment, due to bone-marrow toxicity. On lowering the dosage or discontinuing the drug TK returned to basal levels. Although the rise in serum may well not be correlated only with the HIV infection, it does add to the picture given by other clinical and/or laboratory methods. Serum TK can be a helpful laboratory test in the follow-up of patients with HIV infection, especially when serum levels are disproportionate to the stage, opportunistic infections, lymphoproliferative malignancies. In such cases bone-marrow toxicity due to treatment can be suspected.     

The basics of preclinical drug development for neurodegenerative disease indications

Background

Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV-infected patients.

Methods

In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPα and sAPPβ), amyloid beta fragment 1-42 (Aβ_1-42), and total and hyperphosphorylated tau (t-tau and p-tau) in CSF of 86 HIV-infected (HIV+) subjects, including 21 with AIDS dementia complex (ADC), 25 with central nervous system (CNS) opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV-) subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease.

Results

CSF sAPPα and sAPPβ concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Aβ_1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections.

Conclusions

Parallel reductions of CSF sAPPα and sAPPβ in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease.     

KIR/HLA pleiotropism: protection against both HIV and opportunistic infections

The compound genotype KIR3DS1/HLA-B Bw4-80I, which presumably favors natural killer cell activation, has been implicated in protection against HIV disease. We show that this genotype confers dual protection over the course of HIV disease; early direct containment of HIV viral load, and late specific defense against opportunistic infections, but not AIDS-related malignancies. The double protection of KIR3DS1/Bw4-80I in an etiologically complex disease such as AIDS, along with the disease specificity of its effects is conceptually novel and underscores the intricacy of host immunogenetics against HIV/AIDS.     

Some Opportunistic Parasitic Infections in AIDS: Candidiasis, Pneumocystosis, Cryptosporidiosis, Toxoplasmosis

Almost 80% of patients with AIDS die from infections other than human immunodeficiency virus (HIV). These infections usually occur late in the course of disease when CD4(+) T-cell count has fallen below 200 permm(3) cells per milliliter. Most of these infections are caused by organisms that do not normally afflict healthy individuals and are thus considered to be opportunistic. In this article, Lloyd Kasper and Dominique Buzoni-Gatel review the host-parasite interaction for four important pathogens: Candida albicans and Pneumocystis carinii (usually non-invasive pathogens), Cryptosporidium parvum (invades the cells but remains localized in the gut) and Toxoplasma gondii (penetrates through the gut to cause systemic infection). These organisms, which generally cause limited or even insignificant clinical evidence of infection in the normal host, were chosen because of their high prevalence in AIDS patients and because they exhibit different invasive abilities. The reason why individuals with AIDS are susceptible to this particular group of pathogens is uncertain.     

AIDS in Haitian immigrants and in a Caucasian woman closely associated with Haitians.

In Montreal the acquired immune deficiency syndrome (AIDS) was seen in eight Haitian immigrants and one Caucasian woman who had lived with Haitian immigrants for 3 years before the onset of her illness. AIDS was characterized by opportunistic infections alone in seven patients, by opportunistic infection and Kaposi''s sarcoma in one patient and by chronic generalized lymphadenopathy in one patient. Five of the patients had presented with Mycobacterium tuberculosis infections 1 to 12 months before the onset of opportunistic infections. All nine patients were found to have recall anergy by skin testing for delayed hypersensitivity. Enumeration of the lymphocyte subpopulations in three patients showed a marked inversion of the ratio of helper to suppressor T lymphocytes. Six of the patients died as a result of the opportunistic infections; autopsies showed no recognizable causes of immunodeficiency. Thus, there is in Montreal a third clustering of AIDS cases in North America related to Haitian immigrants.     

Penicillium marneffei Infection: Knowledge, Gaps, and Future Directions

Penicilliosis is a disease caused by Penicillium marneffei, a fungus endemic to Southeast Asia. Prior to the HIV/AIDS epidemic, infection was exceedingly rare, but penicilliosis is currently one of the most common opportunistic infections in persons with HIV/AIDS in some Asian countries. This paper describes the clinical manifestations, diagnosis, and epidemiology of this emerging opportunistic infection and will focus on some gaps in our knowledge and directions for future research.     

Biochemical deficiencies of coenzyme Q10 in HIV-infection and exploratory treatment

AIDS patients (2 groups) had a blood deficiency (p less than 0.001) of coenzyme Q10 vs. 2 control groups. AIDS patients had a greater deficiency (p less than 0.01) than ARC patients. ARC patients had a deficiency (p less than 0.05) vs. control. HIV-infected patients had a deficiency (p less than 0.05) vs. control. The deficiency of CoQ10 increased with the increased severity of the disease, i.e., from HIV positive (no symptoms) to ARC (constitutional symptoms, no opportunistic infection or tumor) to AIDS (HIV infection, opportunistic infection and/or tumor). This deficiency, a decade of data on CoQ10 on the immune system, on IgG levels, on hematological activity constituted the rationale for treatment with CoQ10 of 7 patients with AIDS or ARC. One was lost to follow-up; one expired after stopping CoQ10; 5 survived, were symptomatically improved with no opportunistic infection after 4-7 months. In spite of poor compliance of 5/7 patients, the treatment was very encouraging and at times even striking.     

Opportunistic infection as a cause of transient viremia in chronically infected HIV patients under treatment with HAART

When highly active antiretroviral therapy is administered for long periods of time to HIV-1 infected patients, most patients achieve viral loads that are “undetectable” by standard assay (i.e., HIV-1 RNA < 50 copies/ml). Yet despite exhibiting sustained viral loads below the level of detection, a number of these patients experience unexplained episodes of transient viremia or viral “blips”. We propose here that transient activation of the immune system by opportunistic infection may explain these episodes of viremia. Indeed, immune activation by opportunistic infection may spur HIV replication, replenish viral reservoirs and contribute to accelerated disease progression. In order to investigate the effects of intercurrent infection on chronically infected HIV patients under treatment with highly active antiretroviral therapy (HAART), we extend a simple dynamic model of the effects of vaccination on HIV infection [Jones, L.E., Perelson, A.S., 2002. Modeling the effects of vaccination on chronically infected HIV-positive patients. JAIDS 31, 369–377] to include growing pathogens. We then propose a more realistic model for immune cell expansion in the presence of pathogen, and include this in a set of competing models that allow low baseline viral loads in the presence of drug treatment. Programmed expansion of immune cells upon exposure to antigen is a feature not previously included in HIV models, and one that is especially important to consider when simulating an immune response to opportunistic infection. Using these models we show that viral blips with realistic duration and amplitude can be generated by intercurrent infections in HAART treated patients.     

HIV感染中的细胞凋亡

CD4^ T细胞的丢失在HIV感染引起免疫缺陷过程中起着重要作用。但造成CD4^ T细胞丢失的具体机制还不清楚,细胞凋亡可能是CD4^ T细胞丢失的一个重要因素,HIV感染以后,病毒蛋白的持续性产出导致免疫系统的持续性激活,引起Th1细胞的丢失,Th1细胞通过合成Ⅰ型细胞因子,抑制淋巴细胞的自发凋亡,另外,病毒蛋白或其他因素能够使CD4^ ,CD8^ T细胞和APC转化为凋亡的效应细胞,通过Fas/FasL或其他途径引起细胞凋亡,HIV感染人体后凋亡细胞不仅有CD4^ T细胞,还包括B细胞,NK细胞,粒细胞,神经细胞和单细胞,凋亡作为机体的自我防护措施,在清除感染细胞的同时,并没有抑制HIV在单细胞/巨噬细胞内的复制,反而造成大量未感染细胞的凋亡,导致对HIV复制的失控,发展为严重的免疫缺陷,引起AIDS相关的机会性感染。     

The spleen in HIV infection — morphological evidence of HIV-associated macrophage dysfunction

One-hundred spleens from HIV-infected patients which were studied by conventional morphological and immunohistochemical methods exhibited alterations in lymphatic tissue as well as in the mononuclear phagocyte system (MPS): these were probably related directly to HIV infection of lymphocytes and MPS cells. There was ample evidence of impairment of macrophage activation, accompanied by decreased expression of functional markers and an enhanced reactivity with antibodies against S100 protein. This impairment of macrophage function is related to the particular morphology and aggressive clinical behaviour of some opportunistic infections in AIDS.     

Leishmania, Trypanosoma and monoxenous trypanosomatids as emerging opportunistic agents

Immunosuppression is associated with the occurrence of a large variety of infections, several of them due to opportunistic protozoa. The parasitic protozoa of the family Trypanosomatidae vary greatly in their importance as potential opportunistic pathogens. African trypanosomiasis is no more common nor severe during AIDS. The situation with Chagas' disease, however, is much different. Although the process is not clearly understood, there appears to be a reactivation of Trypanosoma cruzi infection, which can lead to severe meningoencephalitis. In persons with AIDS, leishmaniasis is often exacerbated, particularly Leishmania infantum, which causes visceral leishmaniasis in southern Europe. Since 1990, 1,616 cases of visceral leishmaniasis/HIV co-infection have been reported, mainly from southern Europe, and particularly from Spain, southern France, and Italy. The co-infected patients are primarily young adults and belong to the risk group of intravenous drug users. Isoenzymatic identification of 272 isolates showed 18 different L. infantum zymodemes, of which 10 represent new zymodemes hitherto found only during HIV co-infection. New foci of co-infection are emerging in various parts of the world, including Brazil and East Africa. Moreover, since 1995, non-human monoxenous trypanosomatids have been found in AIDS patients, causing both diffuse cutaneous lesions and visceral infections. In countries where visceral leishmaniasis is endemic, particularly in southern Europe, immunosuppressive treatments for organ transplants or malignant diseases often result either in reactivation of asymptomatic visceral leishmaniasis or in facilitation of new infections.     

The neurobiology of human immunodeficiency virus infections

A variety of diseases of the central and peripheral nervous systems evolves during the course of human immunodeficiency virus (HIV) infections. Most are not related to documented opportunistic infections and may be the direct result of HIV infections, as large proportions of healthy and ill HIV-infected persons show evidence of nervous system infection. These diseases occur at different times during the infection and have diverse inflammatory, demyelinating, or degenerative pathological features that suggest different pathogenetic mechanisms. The route and determinants of HIV invasion of the nervous system are unknown. Within the brain, viral antigen and RNA are found predominantly in macrophages, but the reason why profound dementia and cortical atrophy result from this infection remains a mystery. By analogy to other lentivirus infections, particularly visna virus in sheep, neuropathological changes may be mediated by cytokines. Other possible pathogenetic mechanisms include toxicity of viral polypeptides, transactivation of viral or cellular genes, autoimmunity, or other opportunistic infections. Clarification of the pathogenesis of HIV-related diseases is critical to the design of rational therapies.     

Mucosal transmission and induction of simian AIDS by CCR5-specific simian/human immunodeficiency virus SHIV(SF162P3)

Nonhuman primate models are increasingly used in the screening of candidate AIDS vaccine and immunization strategies for advancement to large-scale human trials. The predictive value of such macaque studies is largely dependent upon the fidelity of the model system in mimicking human immunodeficiency virus (HIV) type 1 infection in terms of viral transmission, replication, and pathogenesis. Herein, we describe the efficient mucosal transmission of a CCR5-specific chimeric simian/human immunodeficiency virus, SHIV(SF162P3). Female rhesus macaques were infected with SHIV(SF162P3) after a single atraumatic application to the cervicovaginal mucosa. The disease course of SHIV(SF162P3)-infected monkeys is similar and as varied as natural HIV infection in terms of viral replication, gradual loss of CD4(+) peripheral blood mononuclear cells, and the development of simian AIDS-defining opportunistic infections. The SHIV(SF162P3)/macaque model should facilitate direct preclinical assessment of HIV vaccine strategies in addition to antiviral compounds directed towards envelope target cell interactions. Furthermore, this controlled model provides the setting to investigate immunologic responses and putative host-specific susceptibility factors that alter viral transmission and subsequent disease progression.     

Persistence of gut mucosal innate immune defenses by enteric α-defensin expression in the simian immunodeficiency virus model of AIDS

Gastrointestinal mucosa is an early target of HIV and a site of viral replication and severe CD4(+) T cell depletion. However, effects of HIV infection on gut mucosal innate immune defense have not been fully investigated. Intestinal Paneth cell-derived α-defensins constitute an integral part of the gut mucosal innate defense against microbial pathogens. Using the SIV-infected rhesus macaque model of AIDS, we examined the level of expression of rhesus enteric α-defensins (REDs) in the jejunal mucosa of rhesus macaques during all stages of SIV infection using real-time PCR, in situ hybridization, and immunohistochemistry. An increased expression of RED mRNAs was found in PC at the base of the crypts in jejunum at all stages of SIV infection as compared with uninfected controls. This increase correlated with active viral replication in gut-associated lymphoid tissue. Loss of RED protein accumulation in PC was seen in animals with simian AIDS. This was associated with the loss of secretory granules in PC, suggesting an increase in degranulation during advanced SIV disease. The α-defensin-mediated innate mucosal immunity was maintained in PC throughout the course of SIV infection despite the mucosal CD4(+) T cell depletion. The loss of RED protein accumulation and secretion was associated with an increased incidence of opportunistic enteric infections and disease progression. Our findings suggest that local innate immune defense exerted by PC-derived defensins contributes to the protection of gut mucosa from opportunistic infections during the course of SIV infection.     

A mathematical model of comprehensive test-and-treat services and HIV incidence among men who have sex with men in the United States

Background

Early diagnosis and treatment of HIV infection and suppression of viral load are potentially powerful interventions for reducing HIV incidence. A test-and-treat strategy may have long-term effects on the epidemic among urban men who have sex with men (MSM) in the United States and may achieve the 5-year goals of the 2010 National AIDS Strategy that include: 1) lowering to 25% the annual number of new infections, 2) reducing by 30% the HIV transmission rate, 3) increasing to 90% the proportion of persons living with HIV infection who know their HIV status, 4) increasing to 85% the proportion of newly diagnosed patients linked to clinical care, and 5) increasing by 20% the proportion of HIV-infected MSM with an undetectable HIV RNA viral load.

Methods and Findings

We constructed a dynamic compartmental model among MSM in an urban population (based on New York City) that projects new HIV infections over time. We compared the cumulative number of HIV infections in 20 years, assuming current annual testing rate and treatment practices, with new infections after improvements in the annual HIV testing rate, notification of test results, linkage to care, initiation of antiretroviral therapy (ART) and viral load suppression. We also assessed whether five of the national HIV prevention goals could be met by the year 2015. Over a 20-year period, improvements in test-and-treat practice decreased the cumulative number of new infections by a predicted 39.3% to 69.1% in the urban population based on New York City. Institution of intermediate improvements in services would be predicted to meet at least four of the five goals of the National HIV/AIDS Strategy by the 2015 target.

Conclusions

Improving the five components of a test-and-treat strategy could substantially reduce HIV incidence among urban MSM, and meet most of the five goals of the National HIV/AIDS Strategy.     

Evidences for Viral Strain Selection in Late Stages of HIV Infection: An Analysis of Vpu Alleles

One of the most studied topics about AIDS disease is the presence of different progression levels in patients infected by HIV. Several studies have shown that this progression is directly associated with host genetics, although viral factors are also known to play a role. Here we explore the contribution of Vpu protein in the evolution of viral population. The sequence variation of Vpu was analyzed during HIV infection in peripheral blood monocyte cells of 12 patients in different clinical stages of HIV-1 infection early and late stages of infections, separated by at least 4 years. The clustering analysis of Vpu sequences showed higher diversity of early alleles, non-random distribution of sequences, and viral evolution strains selection. Forty-two amino acid modifications were found in the multiple alignments of the 57 different alleles found for early stage were 23 modifications were found in the late stage dataset. Interestingly fourteen alteration of early stage were located in conserved site related with Vpu functions alterations while these alterations appear with less frequency in the late stage of infection. Moreover, late stage alleles tend to be similar with the Vpu wild type sequence, suggesting viral selection toward populations harboring more efficient variants during the course of infection. This would contribute to higher infectivity and viral replication actually observed at the aggressive late stages of infection. These data, in conjunction with in vitro experiments, will be important to elucidation of the physiological relevance of Vpu protein in the pathogenic mechanisms of AIDS.     

Temozolomide-related infections: review of the literature

Temozolomide (TMZ) is an alkylating, antineoplastic agent which is being used to treat cases of refractory anaplastic astrocytoma, newly-diagnosed glioblastoma multiforme and metastatic melanoma. TMZ causes lymphopenia and T-cell dysfunction in most of the patients. Related to this toxicity several opportunistic infections have been reported in the literature, but were not well characterized. To further investigate this topic, relevant English language studies were identified through Medline. There were 36 previously reported cases of infection related to TMZ. The median age of the cases was 55 years (range 33-73). The most frequently experienced infections were mucocutaneous candidiasis (n=11; 28.2%), herpes zoster (n=5; 12.8%), herpes simplex virus (n=4; 10.2%), cytomegalovirus (CMV) (n=5; 12.8%), pneumocystis carinii pneumonia (PCP) (n=3; 7.6%), hepatitis B virus (HBV) (n=2; 5.1%) and others (n=9; 23%). Mortality rates were 28.5% (n=4/14) in patients with reported outcome. In this survey, about one third of the TMZ-related severe infections resulted in death. Patients treated with TMZ are at increased risk for opportunistic viral and bacterial infection. Therefore, close monitoring of patients receiving TMZ for opportunistic infections should be carried out.