Myocardial Fibrosis Among Antiretroviral Therapy-Treated Persons With Human Immunodeficiency Virus in South Africa.

BACKGROUND: Heart failure is a prominent cardiovascular disease (CVD) manifestation in sub-Sarahan Africa. Myocardial fibrosis is a central feature of heart failure that we aimed to characterize among persons with human immunodeficiency virus (PWH) in South Africa. METHODS: Cardiovascular magnetic resonance (CMR) imaging was performed among PWH with viral suppression and uninfected controls, both free of known CVD. Plasma levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) were measured. Comparisons by human immunodeficiency virus (HIV) status were made using linear and logistic regression, adjusted for age, sex, and hypertension. RESULTS: One hundred thirty-four PWH and 95 uninfected persons completed CMR imaging; age was 50 and 49 years, with 63% and 67% female, respectively. Compared with controls, PWH had greater myocardial fibrosis by extracellular volume fraction ([ECV] absolute difference, 1.2%; 95% confidence interval [CI], 0.1-2.3). In subgroup analyses, the effect of HIV status on ECV was more prominent among women. Women (vs controls) were also more likely to have elevated NT-proBNP levels (>125 pg/mL; odds ratio, 2.4; 95% CI, 1.0-6.0). Among all PWH, an elevated NT-proBNP level was associated with higher ECV (3.4% higher; 95% CI, 1.3-5.5). CONCLUSIONS: Human immunodeficiency virus disease may contribute to myocardial fibrosis, with an effect more prominent among women. Research is needed to understand heart failure risk among PWH within sub-Saharan Africa.

Assessment of arterial elasticity among HIV-positive participants with high CD4 cell counts: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: Both HIV infection and antiretroviral therapy (ART) may increase cardiovascular disease (CVD) risk. Assessments of vascular function and structure can be used to study the pathogenesis and progression of CVD, including the effects of ART and other interventions. The objective of this report is to understand methods to assess vascular (dys)function and report our experience in the Arterial Elasticity Substudy in the Strategic Timing of AntiRetroviral Treatment (START) trial. METHODS: We review literature and analyze baseline data from the Arterial Elasticity Substudy, which estimated vascular (dys)function through analysis of the diastolic blood pressure (BP) waveform. Linear regression was used to study cross-sectional associations between baseline clinical factors and small or large arterial elasticity. RESULTS: Arterial elasticity measurement was chosen for its improved measurement reproducibility over other methodologies and the potential of small arterial elasticity to predict clinical risk. Analysis of baseline data demonstrates that small artery elasticity is impaired (lower) with older age and differs by race and between geographical regions. No HIV-specific factors studied remained significantly associated with arterial elasticity in multivariate models. CONCLUSIONS: Longitudinal analyses in this substudy will provide essential randomized data with which to study the effects of early ART initiation on the progression of vascular disease among a diverse global population. When combined with future biomarker analyses and clinical outcomes in START, these findings will expand our understanding of the pathogenesis of HIV-related CVD.

Human herpesvirus 6-meningoencephalitis in an HIV patient with progressive multifocal leukoencephalopathy.

Human herpesvirus 6 (HHV6) has been reported as a rare cause of meningoencephalitis and leukoencephalitis. We present an HIV-infected patient with lesions of progressive multifocal leukoencephalopathy (PML), but also meningoencephalitis apparently due to HHV6. Immunohistochemistry for HHV6 antigens and in situ polymerase chain reaction for HHV6 genome showed many positive lymphocytes and microglia in the meningeal and cortical lesions. More importantly, dead and dying neurons were conspicuous; some were undergoing neuronophagia and some displayed evidence of HHV6 infection. A pathogenic role for this almost universal, and usually commensal, virus in inflammatory brain lesions and PML is briefly discussed.

The HHV6 paradox: ubiquitous commensal or insidious pathogen? A two-step in situ PCR approach.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) and multiple sclerosis (MS) are demyelinative diseases of the central nervous system (CNS). PML occurs mostly in individuals with AIDS-impaired immunity and is thought to be caused by JC polyoma virus (JCV). In MS a neurotrophic virus trigger is suspected, but the precise etiology remains unknown. Human herpesvirus 6 (HHV6) is a ubiquitous, commensal and usually benign beta-herpesvirus. Some researchers have found evidence for HHV6 infection in MS plaques and sera. We recently demonstrated a high frequency of cells containing HHV6 genome in PML lesions, as well as co-infection of oligodendrocytes by JCV and HHV6. This suggests that HHV6 may be a co-factor in the etiology of PML, and raises questions about its role in other demyelinative diseases. OBJECTIVES: To determine the prevalence and cellular localization of HHV6, JCV and HIV-1 infected cells in PML, MS, AIDS and control CNS tissues, and their potential relationship with disease. STUDY DESIGN: An unconventional, sensitive two-step in situ polymerase chain reaction (ISPCR) procedure was used to amplify and detect HHV6, JCV and HIV-1 genomic DNAs in formalin fixed, paraffin-embedded archival CNS tissues. HHV6, JCV and HIV-1 gene expression was detected by ICC for HHV6 p41 and gp101, JCV large T, and HIV-1 p24 gag and NEF proteins. RESULTS: A high frequency of HHV6 genome was consistently detected in both PML and MS white matter lesional cells; a peri-lesional concentration was notable. HHV6 was found mainly in oligodendrocytes, but neurons were also infected. HHV6 was present in larger amounts than JCV in PML lesions, while more HIV-1 than HHV6 was present in AIDS. Variable amounts of HHV6 genome were detected in normal, AIDS and other control brains; the frequency of infected cells tended to increase with patient age. CONCLUSIONS: High concentrations of HHV6 genome in association with PML and MS lesions, open the possibility that HHV6 activation may play a role in the pathogenesis of these demyelinative diseases.

Association of human herpesvirus 6 with the demyelinative lesions of progressive multifocal leukoencephalopathy.

Progressive Multifocal Leukoencephalopathy (PML) is a primary demyelinating disease of the central nervous system occurring almost exclusively in individuals with impaired cell-mediated immunity. The JC polyoma virus has been accepted as the etiologic agent ofPML. Using a two-step in-situ polymerase chain reaction procedure to amplify and detect genomic DNA of human herpesvirus-6 (HHV6) in formalin-fixed paraffin-embedded archival brain tissues, a high frequency of infected cells was consistently detected in PML white matter both within and surrounding demyelinative lesions and HHV6 genome was found mainly within oligodendrocytes. Lesser amounts of HHV6 genome were detected in most normal, AIDS, and other neurological disease control tissues. Immunocytochemistry for HHV6 antigens showed actively infected nuclei of swollen oligodendrocytic morphology only within the demyelinative lesions of PML but not in adjacent uninvolved tissue. In addition, no HHV6 antigens were detectable in control tissues including brains of individuals with HIV-1 encephalopathy but without PML. Double immunohistochemical staining for JC virus large T antigen and HHV6 antigens demonstrated co-labeling of many swollen intralesional oligodendrocytes in the PML cases. The evidence suggests that HHV6 activation in conjunction with JC virus infection is associated with the demyelinative lesions of PML.

Age related rejoining of broken chromosomes in human leukocytes following X-irradiation.

One theory of aging is that the ability to repair DNA or chromosome damage decreases with age. This study made use of a method which allows the measurement of chromatid repair in interphase nuclei, the technique of premature chromosome condensation. The number of excess chromosome fragments per cell remaining after 24 h of incubation at 37 degrees C was determined and used as a measure of the ability of leukocytes to repair. The leukocytes from male donors of several ages were used and the cells from older donors showed greater residual damage and, therefore, less repair.

A means of retaining chromosome damage in irradiated human lymphocytes.

The method of premature chromosome condensation has been used to determine the damage induced by ionizing radiation to chromosomes in G1 human lymphocytes. The method has also demonstrated the repair of such damage with time following exposure. This study shows how storage at a cold temperature can be used to retain this damage for further biodosimetric study.

Adenosine 3',5'-monophosphate (cAMP)-binding protein and cAMP-dependent protein kinase in human placenta.

cAMP modulates estrogen, hCG, and lactate syntheses by human placenta, cAMP presumably exerts its major intracellular effect by binding to cAMP-dependent protein kinase (cAMP-PK), which, in turn, phosphorylates regulatory proteins within the target cell. cAMP binding and cAMP-PK have not been previously identified in placenta. [3H]cAMP binding to crude cytosol fractions of term placenta was rapid, saturable, and reversible. Scatchard analyses of saturation experiments of [3H]cAMP binding to placental cytosol were linear (Kd = 1.13 +/- 0.11 x 10(-8) M; n = 5). The binding capacity was 1.27 +/- 0.18 pmol/mg protein. Competition for the [3H]cAMP-binding site followed the potency order cAMP much greater than cGMP much greater than (Bu)2cAMP, analogous to cAMP binding to cAMP-PK in other tissues. ADP, ATP, and adenosine did not compete for the [3H]cAMP-binding site. cAMP significantly enhanced phosphorylation of histone protein by placental cytosol (activity ratio, 0.57 +/- 0.04; P less than 0.01). Two peaks of [3H]cAMP binding and coincident cAMP-PK activity were identified by DEAE-cellulose column chromatography of placental cytosol corresponding to classical type I and type II cAMP-PK. While the majority of the cAMP-PK was found in placental cytosol, cAMP-PK was also demonstrated in crude microsomal and microvillous brush border membranes of human placenta after solubilization with Triton X-100 (P less than 0.05). Regulation of placental function by catecholamines and other hormones known to mediate cAMP levels may be accomplished through the phosphorylation of cellular proteins by cAMP-dependent protein kinases.