System In HIV-infected Patients Research Articles

Microbial Protein Binding to gC1qR Drives PLA2G1B-Induced CD4 T-Cell Anergy.

The origin of the impaired CD4 T-cell response and immunodeficiency of HIV-infected patients is still only partially understood. We recently demonstrated that PLA2G1B phospholipase synergizes with the HIV gp41 envelope protein in HIV viremic plasma to induce large abnormal membrane microdomains (aMMDs) that trap and inactivate physiological receptors, such as those for IL-7. However, the mechanism of regulation of PLA2G1B activity by the cofactor gp41 is not known. Here, we developed an assay to directly follow PLA2G1B enzymatic activity on CD4 T-cell membranes. We demonstrated that gp41 directly binds to PLA2G1B and increases PLA2G1B enzymatic activity on CD4 membrane. Furthermore, we show that the conserved 3S sequence of gp41, known to bind to the innate sensor gC1qR, increases PLA2G1B activity in a gC1qR-dependent manner using gC1qR KO cells. The critical role of the 3S motif and gC1qR in the inhibition of CD4 T-cell function by the PLA2G1B/cofactor system in HIV-infected patients led us to screen additional microbial proteins for 3S-like motifs and to study other proteins known to bind to the gC1qR to further investigate the role of the PLA2G1B/cofactor system in other infectious diseases and carcinogenesis. We have thus extended the PLA2G1B/cofactor system to HCV and Staphylococcus aureus infections and additional pathologies where microbial proteins with 3S-like motifs also increase PLA2G1B enzymatic activity. Notably, the bacteria Porphyromonas gingivalis, which is associated with pancreatic ductal adenocarcinoma (PDAC), encodes such a cofactor protein and increased PLA2G1B activity in PDAC patient plasma inhibits the CD4 response to IL-7. Our findings identify PLA2G1B/cofactor system as a CD4 T-cell inhibitor. It involves the gC1qR and disease-specific cofactors which are gC1qR-binding proteins that can contain 3S-like motifs. This mechanism involved in HIV-1 immunodeficiency could play a role in pancreatic cancer and several other diseases. These observations suggest that the PLA2G1B/cofactor system is a general CD4 T-cell inhibitor and pave the way for further studies to better understand the role of CD4 T-cell anergy in infectious diseases and tumor escape.

Features of diagnosis of inflammatory lesions of central nervous system in HIV-infected patients at terminal stage of disease: clinical case

The authors of the article describe a case of the damage to the central nervous system by fungi of the genus Cryptococcus in a HIV-infected patient. The features of clinical manifestations and laboratory diagnostics are characterized. Special attention is paid to the discrepancy between the sharply changed appearance of the cerebrospinal fluid obtained during lumbar puncture and the clinical picture of the disease as well as the data of laboratory analysis of cerebrospinal fluid.

Оценка влияния клинических аспектов течения сочетанной патологии (ВИЧ-инфекция и туберкулез) на распространение микобактерий туберкулеза в очагах, как одного из основных факторов риска инфекции

Introduction: The article presents an analysis of the state of the immune system of HIV-infected patients with tuberculosis, the rate of recurrence of tuberculosis in HIV-infected people against the background of insufficient preventive therapy against HIV-infection and tuberculosis. Aim: To assess the effect of clinical aspects of the course of combined pathology (HIV infection and tuberculosis) on the spread of isolation of bacteria of tuberculosis mycobacteria as one of the main risk factors for infection in foci. Materials and methods: comparative analysis of isolation of bacteria of tuberculosis mycobacteria among patients with combined pathology (tuberculosis and HIV) was carried out (main group): determination of CD4 lymphocyte cell number and isolation of tuberculosis mycobacteria (n = 100). The number of TB recurrences in the main group (100 patients) and comparison group (TB patients) – 100 patients were studied. Data processing was carried out using the calculation of intensive and extensive indicators, the calculation of the standard error of the average (m). Statistical analysis was performed using Microsoft Excel. The results testified: the impact of the clinical course in tuberculosis patients with HIV infection characterized by an immunodeficiency condition, the presence of stages of 4B and 4V HIV infection (65,0 (95% RI:55;74)) and the recurrent course of tuberculosis in 25% (95 RI:17,5;34) is 1.4 times higher than in tuberculosis and is one of the main risk factors for infection in foci.

Experience with 13-valent conjugated pneumococcal vaccine in HIV-infected patients

Evaluate the effect of PCV13 vaccination on the composition of the microflora of the upper respiratory tract and the immune system in HIV-infected patients. 100 patients with HIV-infection were included in the study. The patients underwent immunological examination and the collection of biomaterial from the posterior pharyngeal wall for microbiological examination. After obtaining the results of the examinations, PCV13 was intramuscularly administered. 7 days after the introduction of the vaccine, an assessment of adverse events was carried out, after 3 months, microbiological and immunological examinations were repeated. Immediately after the administration of PCV13, 5% of patients felt pain during the administration. Local reactions were reported in 6 patients. One participant showed a rise in temperature to 38.3C over 2 days. Before vaccination, 16 strains of S. pneumoniae were seeded in patients. 3 months after the administration of PCV13, pneumococcus was isolated in 8 patients. 3 months after immunization, the median level of populations and subpopulations of lymphocytes became higher than the pre-vaccination. Our results show high risk of pneumococcal infections in HIV-positive patients. A tendency towards a decrease in the level of S. pneumoniae carriage was revealed 3 months after the administration of PCV13. The high level of enterobacteria carriage in HIV-positive patients is noteworthy. There is a pronounced positive effect from the use of PCV13 in HIV-positive patients on cellular factors of the immune system. The use of PCV13 is a safe and effective method for the prevention of S. pneumoniae infections.

SOME ASPECTS OF MANAGEMENT OF HIV-INFECTED PATIENTS WITH PATHOLOGY OF DIGESTIVE SYSTEM IN CONTEXT OF FAMILY MEDICINE PRACTICE

Introduction. In the current situation of the HIV-infection epidemic, every 100-th citizen of Ukraine aged between 15 and 49 is infected with HIV. It is one of the highest rates among countries in the European Region. The issue of retaining HIV-positive patients in the medical surveillance system and support for adherence to ART treatment are becoming particularly relevant. At the same time, the comorbidity of HIV-infection with digestive system lesion is one of the main elements of pathological changes, both in the progression of HIV infection and in the occurrence of various complications leading to interruptions or failure to receive continuous antiretroviral therapy (ART). The purpose of the study is to examine the features of the digestive system lesions of HIV-infected patients and their impact on the effectiveness of antiretroviral therapy. Materials and methods. The study was conducted on randomly selected 215 HIV-infected patients in compliance with the bioethical and scientific standards, in accordance with industry standards and clinical guidelines approved by the Ministry of Health of Ukraine. Results and Discussion. Patients were divided into two comparison groups: the main group (MG) had 158 (73.5%) of HIV-infected persons with pathology of the digestive system, the controlled group (СG) had 57 (26.5%) of HIV-infected patients with no signs of gastric lesions of the gastrointestinal tract. Among the lesions of the digestive system in HIV-infected patients, hepatitis of viral and/or toxic genesis, chronic inflammatory diseases of the esophagus and gastroduodenal zone, chronic pancreatitis and cholecystitis were most often observed. In 61.4%, the pathology of the digestive tract was combined. When evaluating the efficacy of ART, no statistical difference was found between MG and CG in the frequency of the virologic response and the level of viral load at the beginning of the study and at 6 months of follow-up. However, MG patients had a worse immunologic response compared to CG, they were significantly more likely to switch the initial ART regimen, have breaks in treatment and development of adverse reactions. Patients treated for comorbid digestive system disorders had ART replacements less frequently and after 6 months of treatment they had an average level of CD4 + lymphocytes, which corresponded to the normal value. Conclusions. A significant majority of the examined patients with HIV-infection had digestive system lesions (73.5%). HIV-infected patients with digestive system pathology had more treatment interruptions, switch of ART regimens, and a worse immunological response, compared with the controlled group. Untreated diseases of the digestive system could be predictors of an increased break rate of ART, switch of treatment regimens, and decreased treatment efficacy. The introduction of an integrated, patient-oriented approach to the management of these nosologies in family medicine practice is proposed.

Prognosis of fungal infection of central nervous system in HIV-infected patients: a retrospective study of 77 patients in Ukraine

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Lytvyn K, Shostakovych-Koretskaya L, Doroshenko A, Andreeva T. Prognosis of fungal infection of central nervous system in HIV-infected patients: a retrospective study of 77 patients in Ukraine. HIV & AIDS Review. International Journal of HIV-Related Problems. 2019;18(2):92-99. doi:10.5114/hivar.2019.86373. APA Lytvyn, K., Shostakovych-Koretskaya, L., Doroshenko, A., & Andreeva, T. (2019). Prognosis of fungal infection of central nervous system in HIV-infected patients: a retrospective study of 77 patients in Ukraine. HIV & AIDS Review. International Journal of HIV-Related Problems, 18(2), 92-99. https://doi.org/10.5114/hivar.2019.86373 Chicago Lytvyn, Kateryna Y., Liudmyla R. Shostakovych-Koretskaya, Anna A. Doroshenko, and Tatiana I. Andreeva. 2019. "Prognosis of fungal infection of central nervous system in HIV-infected patients: a retrospective study of 77 patients in Ukraine". HIV & AIDS Review. International Journal of HIV-Related Problems 18 (2): 92-99. doi:10.5114/hivar.2019.86373. Harvard Lytvyn, K., Shostakovych-Koretskaya, L., Doroshenko, A., and Andreeva, T. (2019). Prognosis of fungal infection of central nervous system in HIV-infected patients: a retrospective study of 77 patients in Ukraine. HIV & AIDS Review. International Journal of HIV-Related Problems, 18(2), pp.92-99. https://doi.org/10.5114/hivar.2019.86373 MLA Lytvyn, Kateryna Y. et al. "Prognosis of fungal infection of central nervous system in HIV-infected patients: a retrospective study of 77 patients in Ukraine." HIV & AIDS Review. International Journal of HIV-Related Problems, vol. 18, no. 2, 2019, pp. 92-99. doi:10.5114/hivar.2019.86373. Vancouver Lytvyn K, Shostakovych-Koretskaya L, Doroshenko A, Andreeva T. Prognosis of fungal infection of central nervous system in HIV-infected patients: a retrospective study of 77 patients in Ukraine. HIV & AIDS Review. International Journal of HIV-Related Problems. 2019;18(2):92-99. doi:10.5114/hivar.2019.86373.

Заболевания центральной нервной системы у ВИЧ-инфицированных пациентов

Заболевания центральной нервной системы у ВИЧ-инфицированных пациентов

Derivation and validation of an exclusive pre-operative risk evaluation system in HIV-infected patients undergoing surgery

Background: A broadly applicable scoring tool for risk evaluation in HIV-infected surgical patients is imperative for improving outcomes and patient safety. Because sepsis has been considered as the major cause of mortality for HIV-infected post-surgical patients, the objective of this study was to develop a pre-operative risk stratification model that predicts the incidence of sepsis after surgical operations in HIV-infected patients. Methods: The scoring model was created by using inpatient databases, including 762 HIV-infected patients who underwent various surgical procedures from 2008 to 2014 in the Shanghai Public Health Clinical Center (SPHCC). A risk-point scale was developed with five variables for their predictive value of sepsis incidence using single and multi-factor logistical regressions. This model was validated with a receiver operating characteristic (ROC) curve with a Zhengzhou Sixth People Hospital (ZSPH) dataset (182 HIV-infected cases). Results: Post-operative sepsis was identified in 256 patients in the SPHCC dataset. The average total scores of the sepsis group and the non-sepsis group were 7.22 and 11.62, respectively. Using the predictive model of multi-factor logistical regression, the sensitivity and specificity were 0.95 and 93.6, respectively. The area under curve (AUC) score was 0.98[0.97, 0.99]. The result was much larger than five single-factor predicting models. In the 30 days after surgery, 15 patients died, and the mortality rate was around 2% in SPHCC. Post-operative sepsis was identified in 41 patients in the ZSPH dataset, and four sepsis patients died in the 30 days following surgery. The mortality was also around 2% at ZSPH. The AUC score of the same model was 0.86[0.82, 0.93]. Conclusion: The risk scoring system with the predictive model has high predictive accuracy. This indicates that it can help surgeons evaluate the incidence and risk of post-surgical sepsis before surgical procedures on HIV-infected patients.

The frequency and characteristics of cardiovascular pathology in HIV-infected patients (according to aytopsy)

Aim to study the frequency and structure of the cardiovascular diseases (CVD) deaths from HIV-infected patients. A retrospective analysis of medical records of 346 deaths of HIV-infected patients: 225 (65%) males (95% confidence interval - 95% CI 69,8-58,8) and 121 (35%) women (95% CI 30,1-40,1) at the age of 35.0 [32,0;38,0] years. Autopsy was performed in 150 (43,5%) patients (95% CI 38,2-48,6). GCC is installed in 77 (22.3 %) of 346 cases (95% CI of 18.2-26.9) . While 18 (5,2%) patients (95% CI 3,3-8,1) CVD was the main cause of death in 59 (17,1%) - concomitant diseases (95% CI 13,5-1,4). The structure of the CVD were presented with acute heart failure in 17 (4,9%) autopsy cases (95% CI 3,1-7,7) , hydropericardium - 14 (4.0%) of cases (95% CI 2,4-6,7), coronary heart disease in 14 (4.0%) of cases (95% CI 2,4-6,7), cardiomyopathy in 11 (3,2%) cases (95% CI 1,8-5,6), myocarditis in 10 (2.9%) cases (95% CI 1,6-5,2), infective endocarditis in 4 (1.2%) cases (95% CI 0.5-3.0), chronic pulmonary heart, in 4 (1.2%) cases (95% CI 0.5-3.0), effusion in 3 (0.9%) cases (95% CI 0,3 - 2,5). The defeat of the cardiovascular system in HIV-infected patients in 79,2% of cases were formed against the background of generalized of severe opportunistic infections and diseases. In patients not receiving antiretroviral therapy, have higher rates of death AIDS-associated CVD as compared to that in patients receiving therapy: 3,8% (95% CI 1.9-7,3) and 0 respectively (p=0.05).

Immune reconstitution inflammatory syndrome associated with pulmonary pathogens.

Immune reconstitution inflammatory syndrome (IRIS) is an exaggerated immune response to a variety of pathogens in response to antiretroviral therapy-mediated recovery of the immune system in HIV-infected patients. Although IRIS can occur in many organs, pulmonary IRIS, associated with opportunistic infections such as Mycobacterium tuberculosis and Pneumocystis jirovecii, is particularly associated with high morbidity and mortality. The pathology of IRIS is associated with a variety of innate and adaptive immune factors, including CD4+ T-cells, CD8+ T-cells, γδ T-cells, natural killer cells, macrophages, the complement system and surfactant proteins, Toll-like receptors and pro-inflammatory cytokines and chemokines. Although there are numerous reports about the immune factors involved in IRIS, the mechanisms involved in the development of pulmonary IRIS are poorly understood. Here, we propose that studies using gene-deficient murine and nonhuman primate models will help to identify the specific molecular targets associated with the development of IRIS. An improved understanding of the mechanisms involved in the pathology of pulmonary IRIS will help to identify potential biomarkers and therapeutic targets in this syndrome.

ОПЫТ НЕЙРОХИРУРГИЧЕСКОЙ ПОМОЩИ вич-ПОЗИТИВНЫМ БОЛЬНЫМ С ЛОКАЛЬНЫМИ ФОРМАМИ ТУБЕРКУЛЕЗА ЦЕНТРАЛЬНОЙ НЕРВНОЙ СИСТЕМЫ

Goal of the study: to define the interaction procedure between phthisiologists and neurosurgeons when managing local tuberculosis of central nervous system in HIV-infected patients. Materials and methods. Histological, mycobacteriologic and X-ray features of CNS tuberculosis were studied in 73 died and 5 operated HIV-infected patients. Results. Stepwise treatment of the patients with local HIV-associated tuberculous lesions of brain includes conservative treatment with the search for the causative agent in all available biological liquids, and should the therapy fail then the decision is made about biopsy for diagnosis confirmation and sensitivity testing and the consequent decision about surgery aimed to remove the lesion. The surgery can be performed only after the relevant anti-bacterial treatment in compliance with drug sensitivity data till perifocal edema is not visible on the brain images.

Monitoring the Viral Load in HIV Patients under Anti-Retroviral Therapy ( Art )

Viral load monitoring is an important factor in managing HIV disease. Antiretroviral therapy is the recommended treatment for HIV patients, and the goal therapy is achieving viral suppression and reducing viral load below the level of detection. Viral load is an important parameter used to monitor the progression of HIV and critically regarding treatment decision. The results of present study revealed that there were statistical significant differences between patients maintained on treatment (GA) and patients without treatment (GB) regarding the viral load, and clearly indicated that adherence to ART playing a role in suppression the viral load supporting the immune system of HIV infected patients. The success of ART for someone living with HIV depends on, starting the treatment at the right time, choosing the right combination of (ART) and monitoring the effectiveness of the treatment through monitoring the vilral load.

MONITORING THE VIRAL LOAD IN HIV PATIENTS UNDER ANTI-RETROVIRAL THERAPY (ART)

Viral load monitoring is an important factor in managing HIV disease. Antiretroviral therapy is the recommended treatment for HIV patients, and the goal therapy is achieving viral suppression and reducing viral load below the level of detection. Viral load is an important parameter used to monitor the progression of HIV and critically regarding treatment decision. The results of present study revealed that there were statistical significant differences between patients maintained on treatment (GA) and patients without treatment (GB) regarding the viral load, and clearly indicated that adherence to ART playing a role in suppression the viral load supporting the immune system of HIV infected patients. The success of ART for someone living with HIV depends on, starting the treatment at the right time, choosing the right combination of (ART) and monitoring the effectiveness of the treatment through monitoring the vilral load.

Clinical and diagnostic features of the infectious lesions of the central nerve system in hiv-infected patients

Among the observed patients the dominant route of transmission of human immunodeficiency virus (HIV) infection was injecting. The most wide-spread reason of the infection central nervous system (CNS) in HIV-positive patients was Epstein-Barr virus, Toxoplasmosis and Mycobacterium tuberculosis. The disease developed mostly in young patients, regardless of gender. Infectious lesions CNS in HIV-positive patients progressed gradually as well as advanced against the background of clinically sthenic immunodeficiency.

Frequency and Antibiogram of Uropathogens Isolated from Urine Samples of HIV Infected Patients on Antiretroviral Therapy

Opportunistic infections including urinary tract infections (UTIs) are among the predominant cause of morbidity and mortality among HIV infected patients. Persons living with HIV/AIDS (PLWHA) are prone to infection from non-pathogenic microbes in the environment than normal individuals; and this development has been greatly attributed to the weakened immune system of HIV infected patients which makes it difficult to protect the body against invading commensal organisms. In this study, midstream urine (MSU) samples from HIV infected patients who attended the Federal Teaching Hospital Abakaliki (FETHA), Ebonyi State, Nigeria for routine antiretroviral therapy were evaluated by microbiological analysis for uropathogens. Antibiogram was also investigated on all isolated uropathogens by the Kirby-Bauer disk diffusion method. The uropathogens isolated from the MSU of HIV infected patients in this study were identified as: Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae and Proteus mirabilis. S. aureus was the most prevalent isolated organism (n=34). This was followed by K. pneumoniae (n=17), E. coli (16) and P. mirabilis (n=8). All uropathogens produced varying rates of susceptibility and resistance patterns to the tested antibiotics. High sensitivity was observed with gentamicin, ciprofloxacin, ampicillin and amoxycillin-clavulanic acid. Cefotaxime, ceftazidime, cefazolin, ceftriaxone, cefepime, and cefoxitin (which are all 3rd-generation β-lactams) showed less efficacy against the uropathogens. This study draws attention to the increasing rate of UTIs amongst HIV infected patients in Abakaliki metropolis, Ebonyi State of Nigeria, and the resistance of uropathogens to some available antibiotics. Therefore, there is need to checkmate the menace through proper detection and treatment of affected individuals in order to improve the health status of PLWHA in this environment.

The Role of Vitamin D Deficiency in the Pathogenesis of Osteoporosis and in the Modulation of the Immune System in HIV-Infected Patients

Vitamin D deficiency is widespread among HIV-infected adults and children. Vitamin D deficiency may contribute to the risk of developing the long-term complications of HIV infection, such as osteoporosis. Vitamin D is also known to play an important role in the immune system and may affect HIV disease progression and/or CD4 cell counts. This article will review the current data on the role of vitamin D deficiency in the pathogenesis of osteoporosis and in the modulation of the immune system in HIV-infected patients.

HIV, EBV and KSHV: Viral cooperation in the pathogenesis of human malignancies

Malignancies associated with Epstein–Barr virus (EBV) and/or Kaposi’s sarcoma human herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is frequently found in patients infected with HIV. Both these human gammaherpesviruses are known for their oncogenic properties, for the viral products that mimic or interfere with the functions of critical cellular proteins, and the ability to escape the immune responses. The introduction of the highly active anti-retroviral therapy (HAART) has significantly decreased the frequency of Kaposi’s sarcoma (KS), non-Hodgkin’s lymphoma (NHL), and primary central nervous system lymphoma (PCNSL); conversely, for some lymphomas the incidence diminished only slightly, as in Burkitt’s lymphoma (BL), or had no significant variations, as Hodgkin’s lymphoma (HL). These observations may indicate that HAART might have a direct impact on KSHV and EBV biology, that there is a reconstitution of the immune system in HIV-infected patients under HAART, or even that HAART perhaps has a detrimental impact in the pathogenic interactions between HIV, EBV and KSHV. The present review aim to evaluate and to discuss the data available for these hypotheses, in order to shed more light on the mechanisms for the cooperation among HIV-1, EBV and KSHV that may culminate in cell transformation and cancer development in humans.

Homeostatic chemokines CCL19 and CCL21 promote inflammation in human immunodeficiency virus-infected patients with ongoing viral replication

CCL19 and CCL21 and their receptor CCR7 are expressed constitutively within lymphoid organs, regulating lymphocyte homing. Recent studies suggest that these chemokines may have inflammatory properties. We hypothesized a role of CCL19/CCL21 in human immunodeficiency virus (HIV) infection by promoting inflammation. We examined the expression of CCL19 and CCL21 in mononuclear cells from peripheral blood mononuclear cells (PBMC) and bone marrow mononuclear cells (BMMC) in HIV-infected patients before and during highly active anti-retroviral therapy (HAART). We also examined the ability of CCL19/CCL21 to promote inflammatory responses in these patients. PBMC from untreated HIV-infected patients (n = 29) released enhanced levels of CCL19 spontaneously compared with cells from controls (n = 20), particularly in those with symptomatic disease (n = 15, P < 0.01 versus controls). During HAART (n = 9), there was a decrease in the spontaneous CCL19 release and an increase in the phytohaemagglutinin-stimulated CCL19 release in both PBMC (P < 0.01) and BMMC (P < 0.05). In patients with enhanced HIV replication there was an increased proportion of inflammatory CD8(+)CCR7(-)CD45RA(-) T cells in peripheral blood [P < 0.01 and P < 0.05 versus controls, untreated (n = 9) and treatment failure (n = 8), respectively]. In vitro, CCL19/CCL21 promoted an inflammatory response in PBMC when accompanied by high viral load, irrespective of HAART. The HIV-tat protein significantly boosted the inflammatory effect of CCL19/CCL21 in PBMC. These findings link a dysregulated CCL19/CCL21/CCR7 system in HIV-infected patients to persistent inflammation and HIV replication, not only in untreated HIV infection, but also in treatment failure during HAART.

HIV-1 Tat Protein-Induced Rapid and Reversible Decrease in [3H]Dopamine Uptake: Dissociation of [3H]Dopamine Uptake and [3H]2β-Carbomethoxy-3-β-(4-fluorophenyl)tropane (WIN 35,428) Binding in Rat Striatal Synaptosomes

Human immunodeficiency virus (HIV)-1 Tat protein plays a key role in the pathogenesis of both HIV-1-associated cognitive-motor disorder and drug abuse. Dopamine (DA) transporter (DAT) function is strikingly altered in patients with HIV-1-associated dementia and a history of chronic drug abuse. This study is the first in vitro evaluation of potential mechanisms underlying the effects of Tat protein on DAT function. Rat striatal synaptosomes were incubated with recombinant Tat(1-86) protein, and [(3)H]DA uptake and the binding of [(3)H]2beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane (WIN 35,428) and [(3)H]1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine (GBR 12935) were determined. Tat decreased [(3)H]DA uptake, [(3)H]WIN 35,428 binding, and [(3)H]GBR 12935 binding in a time-dependent manner. The potency of Tat for inhibiting [(3)H]DA uptake (K(i) = 1.2 microM) was the same as that for inhibiting [(3)H]GBR 12935 binding but 3-fold less than that for inhibiting [(3)H]WIN 35,428 binding. Mutant Tat proteins did not alter [(3)H]DA uptake. Kinetic analysis of [(3)H]DA uptake revealed that Tat (1 or 10 microM) decreased the V(max) value and increased the K(m) value in a dose-dependent manner. The V(max) value, decreased by Tat (1 microM), returned to the control level after washout of Tat, indicating that the inhibitory effect of Tat on DA uptake was reversible. Saturation studies revealed that Tat decreased the B(max) value and increased the K(d) value of [(3)H]WIN 35,428 binding, whereas Tat decreased the B(max) value of [(3)H]GBR 12935 binding, without a change in the K(d) value. These findings provide new insight into understanding the pharmacological mechanisms of Tat-induced dysfunction of the DAT in the dopaminergic system in HIV-infected patients.

Substantia nigra hyperechogenicity and CSF dopamine depletion in HIV

Dopaminergic dysfunction is thought to play a pivotal role in human immunodeficiency virus (HIV)-related dementia. Decreased dopamine (DA) levels in the cerebrospinal fluid (CSF) and neuronal loss in the substantia nigra (SN) have been reported in HIV-infected patients, suggesting nigrostriatal damage. Structural changes detectable as hyperechogenicity in transcranial ultrasound (TCS) scans of the SN have been reported in patients with Parkinson's disease (PD) and other neurological conditions. In this study, we assessed the echomorphology of the SN in 40 HIV-positive patients compared to 40 age- and sex-matched healthy controls and correlated these findings with CSF levels of DA and the metabolites homovanillic acid (HVA) and 3,4-dihydroxy phenylacetic acid (DOPAC) and with neuropsychologic performance. We observed that the SN of HIV-infected patients was hyperechogenic relative to that of controls (0.07 +/- 0.05 vs. 0.04 +/- 0.07 cm(2); mean +/- SEM; P < 0.001) and that this SN hyperechogenicity was correlated with decreased DA levels in the CSF, decreased CD4 cell count, and an impaired performance in the psychopathology assessment scale (AMDP) subtest for drive and psychomobility. An association to CDC stage, duration of HIV infection, or presence of HIV dementia was not observed. Our results indicate changes in the nigrostriatal system in HIV-infected patients that are detectable as hyperechogenic SN precede prominent extrapyramidal symptoms and cognitive dysfunction.