Humans ; AIDS Dementia Complex/pathology* ; HIV Infections

Background: Antiretroviral treatment (ART) can decreased the incidence of HIV dementia, but milder cognitive impairment may not resolve when patients receive ART. In Indonesia, cognitive screening of HIV patients is not routinely performed before starting ART. Here we assess cognitive impairment in ART- naïve HIV patients beginning treatment in Jakarta. Methods: This is a cross sectional study with inclusion criteria: HIV positive, ART naïve, CD4 T-cells below 200 cells/uL, Karnofsky Performance Score (KPS) above 70. HIV-associated neurocognitive disorder (HAND) was defined by performance at least 1 Standard Deviation (SD) below the mean of demographically adjusted normative scores in at least two cognitive areas. Results: We studied 82 subjects with median (range) age 31 (19-48) years. Fifty six subjects (68%) were males. HAND was found in 42 subjects (51%). Eight subjects (19%) had impairment in 4 domains, 15 subjects (36%) in 3 and 19 (45%) in 2. The most common domain affected was memory (63%). Conclusion: Our results show the prevalence of HAND is high among HIV naïve patients in Jakarta. This establishes the need for screening of cognitive function before initiating ART.
AIDS Dementia Complex ; HIV

OBJECTIVETo explore the role of HIV-1 tat gene variations in AIDS dementia complex (ADC) pathogenesis.

METHODSHIV-1 tat genes derived from peripheral spleen and central basal ganglia of an AIDS patient with ADC and an AIDS patient without ADC were cloned for sequence analysis. HIV-1 tat gene sequence alignment was performed by using CLUSTAL W and the phylogentic analysis was conducted by using Neighbor-joining with MEGA4 software. All tat genes were used to construct recombinant retroviral expressing vector MSCV-IRES-GFP/tat. The MSCV-IRES-GFP/tat was cotransfected into 293T cells with pCMV-VSV-G and pUMVC vectors to assemble the recombinant retrovirus. After infection of gliomas U87 cells with equal amount of the recombinant retrovirus, TNF-α, and IL-1β concentrations in the supernatant of U87 cells were determined with ELISA.

RESULTSHIV-1 tat genes derived from peripheral spleen and central basal ganglia of the AIDS patient with ADC and the other one without ADC exhibited genetic variations. Tat variations and amino acid mutation sites existed mainly at Tat protein core functional area (38-47aa). All Tat proteins could induce U87 cells to produce TNF-α and IL-1β, but the level of IL-1β production was different among Tat proteins derived from the ADC patient's spleen, basal ganglia, and the non-ADC patient's spleen. The level of Tat proteins derived from the ADC patient's spleen, basal ganglia, and the non-ADC patient's spleen were obviously higher than that from the non-ADC patient's basal ganglia.

CONCLUSIONTat protein core functional area (38-47aa) may serve as the key area of enhancing the secretion of IL-1β. This may be related with the neurotoxicity of HIV-1 Tat.

AIDS Dementia Complex ; metabolism ; pathology ; virology ; Adult ; Amino Acid Sequence ; Basal Ganglia ; virology ; Cell Line, Tumor ; Gene Expression Regulation, Viral ; Genes, tat ; HIV-1 ; genetics ; pathogenicity ; Humans ; Interleukin-1beta ; biosynthesis ; genetics ; secretion ; Middle Aged ; Molecular Sequence Data ; Neuroglia ; pathology ; secretion ; Spleen ; virology ; Tumor Necrosis Factor-alpha ; biosynthesis ; genetics ; secretion ; tat Gene Products, Human Immunodeficiency Virus ; genetics ; physiology

INTRODUCTIONHIV-associated neurocognitive disorders (HAND) comprise a wide spectrum of cognitive, motor, and mood abnormalities prevalent in people living with HIV and AIDS (PLWHAs). This field of HIV medicine has gained renewed prominence in recent years with evidence contending that anti-retroviral agents with increased central nervous system (CNS) penetration may improve neurocognitive outcomes in those affected. This review aims at evaluating the available evidence and postulating further study direction in Singapore.

MATERIALS AND METHODSA PubMed search was carried out for original articles and systematic reviews on the subject of HIV-associated neurocognitive disorders, and the results reviewed by the authors.

RESULTSThere is a growing body of evidence that HAND is not uncommon, and the advent of highly active anti-retroviral therapy has increased its prevalence by improving the prognosis of HIV infection, and hence increasing the likelihood of diagnosing of this neurocognitive condition. Screening and diagnosing HAND is important, and requires clinical suspicion as well as validated test batteries for optimal accuracy. The authors recommend strategies for detection in the local context involving stepwise targeted screening. Anti-retroviral agents with good CNS penetration and activity, as well as adjunctive neuro-rehabilitative interventions, may improve the impairments experienced by affected individuals.

CONCLUSIONIncreased awareness of HAND, with earlier diagnosis and targeted, multi-disciplinary management of this challenging condition, may lead to better all-round outcomes for people living with HIV and AIDS in Singapore.

AIDS Dementia Complex ; Anti-HIV Agents ; therapeutic use ; Anti-Retroviral Agents ; therapeutic use ; Antiretroviral Therapy, Highly Active ; HIV Infections ; drug therapy ; Humans ; Neurocognitive Disorders ; Prevalence

BACKGROUNDHIV-1 infected and immune-activated macrophages and microglia secrete neurotoxins, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), which play major role in the neuronal death. It has been shown that different HIV-1 variants have varying abilities to elicit secretion of TNF-α by peripheral blood mononuclear cell (PBMC); however, whether the difference of gp120 gene could affect the secretion of TNF-α and IL-1β by glial cells is unknown. The aim of this study was to explore the association between gene diversity and induction of neurotoxic cytokines.

METHODSIn this study, we constructed retroviral vectors MSCV-IRES-GFP/gp120 using HIV-1 gp120 genes isolated from four different tissues of one patient who died of AIDS dementia complex (ADC). Recombinant retroviruses produced by cotransfection of MSCV-IRES-GFP/gp120, pCMV-VSV-G and pUMVC into 293T cells were collected and added into U87 glial cells. Concentrations of TNF-α and IL-1β secreted by transduced U87 cells were assayed with ELISA separately.

RESULTSThe four HIV-1 gp120 were in the different branch of the neighbor-joining tree. Compared to the pMIG retrovirus (gp120-negative) or U87 cells, all the gp120-positive recombinant retroviruses induced more TNF-α (P < 0.01) and IL-1β (P < 0.01). In addition, compared with the L/MIG retrovirus, all the three brain gp120-positive recombinant retroviruses induced less TNF-α (P < 0.01) and IL-1β (P < 0.01).

CONCLUSIONSHIV-1 gp120 could induce U87 cells secret more TNF-α and IL-1β again. The more important is that difference of HIV-1 gp120, especially cell-tropism may account for the different ability in eliciting secretion of TNF-α and IL-1β, which might supply a novel idea helping understand the pathogenesis of ADC.

AIDS Dementia Complex ; metabolism ; virology ; Cell Line ; Cell Line, Tumor ; Enzyme-Linked Immunosorbent Assay ; HIV Envelope Protein gp120 ; genetics ; metabolism ; Humans ; Interleukin-1beta ; metabolism ; Tumor Necrosis Factor-alpha ; metabolism

The infiltration of monocytes into the CNS represents one of the early steps to inflammatory events in AIDS-related encephalitis and dementia. Increased activity of selected matrix metalloproteinases (MMPs) such as MMP-9 impairs the integrity of blood-brain barrier leading to enhanced monocyte infiltration into the CNS. In this study, we examined the effect of HIV-1 Tat on the expression of MMP-9 in CRT-MG human astroglioma cells. Treatment of CRT-MG cells with HIV-1 Tat protein significantly increased protein levels of MMP-9, as measured by Western blot analysis, zymography and an ELISA. Treatment of CRT-MG cells with HIV-1 Tat protein markedly increased mRNA levels of MMP-9, as analyzed by RT-PCR. Pretreatment of CRT-MG cells with NF-kappaB inhibitors led to decrease in Tat-induced protein and mRNA expression of MMP-9. Pretreatment of CRT-MG cells with MAPK inhibitors suppressed Tat-induced MMP-9 expression. Furthermore, HIV-1 Tat-induced expression of MMP-9 was significantly inhibited by neutralization of TNF-alpha, but not IL-1beta and IL-6. Taken together, our results indicate that HIV-1 Tat can up-regulate expression of MMP-9 via MAPK-NF-kappaB-dependent mechanisms as well as Tat-induced TNF-alpha production in astrocytes.
AIDS Dementia Complex/*metabolism ; Astrocytes/*drug effects/enzymology ; HIV Infections/*complications ; *HIV-1 ; Humans ; Matrix Metalloproteinase 9/*genetics/immunology ; Mitogen-Activated Protein Kinase Kinases/*metabolism ; NF-kappa B/*metabolism ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/immunology/metabolism ; Up-Regulation/drug effects ; tat Gene Products, Human Immunodeficiency Virus/*metabolism

To explore the relationship between the genetic diversity and biological functional site of human immunodeficiency virus HIV-1 gp120 and the pathogenesis of AIDS dementia complex (ADC), the full length sequences of gp120 gene was amplified with PCR from genomic DNA which was extracted from lymphoid and different brain department (periaortic lymphoid, temporal gray/white matter junction, periventricular tissue, choroids plexus, occipital white matter and occipital gray/white matter junction.) of a patient who died of ADC. PCR products were cloned into the pGEM-T vector and positive clones were sequenced. The analysis of neighbor-joining tree, N-glycosylation sites, values of ds/dn, and loop were then all performed. The samples were all identified as HIV-1 B and genetic variation existed in HIV-1 gp120 isolated from different tissues. Compared with standard HIV-1B gp120, biological functional sites of HIV-1 gp120 isolated from the patient changed to some extent. In addition, there were differences in some biological functional sites of HIV-1 gp120 between lymphoid and brain. Therefore, genetic diversity and alterations of some biological functional sites of HIV-1 gp120 might be associated with the pathogenesis of ADC.
AIDS Dementia Complex ; virology ; Amino Acid Sequence ; Genetic Variation ; genetics ; HIV Envelope Protein gp120 ; chemistry ; classification ; genetics ; Humans ; Molecular Sequence Data ; Phylogeny ; Polymerase Chain Reaction ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid

Inflammation, a self-defensive reaction against various pathogenic stimuli, may become harmful self-damaging process. Increasing evidence has linked chronic inflammation to a number of neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis. In the central nervous system, microglia, the resident innate immune cells play major role in the inflammatory process. Although they form the first line of defense for the neural parenchyma, uncontrolled activation of microglia may directly toxic to neurons by releasing various substances such as inflammatory cytokines (IL-1beta, TNF-alpha, IL-6), NO, PGE
alpha-Synuclein/physiology ; Signal Transduction ; Parkinson Disease/*etiology/immunology ; Multiple Sclerosis/etiology ; Models, Biological ; Microglia/immunology/metabolism/*physiology ; Metalloproteases/physiology ; Melanins/physiology ; Matrix Metalloproteinase 3 ; Inflammation Mediators/metabolism ; Humans ; Encephalitis/*etiology/immunology ; Cytokines/secretion ; Animals ; Alzheimer Disease/etiology ; AIDS Dementia Complex/etiology

HIV encephalopathy usually presents with progressive dementia. However the spectrum of neurological manifestations of HIV infection is wide. A 46-year-old man presented with gait disturbance and dysarthria. He was given a neurological examination, which indicated dysarthria, cerebellar ataxia, and pyramidal tract signs. The patient's cognitive functions were intact. On serological study, HIV test was positive. Brain MRI and CSF analyses showed no evidence of tumor or other CNS infection. The patient was treated with highly active anti-retroviral therapy. Three months after treatment, cerebellar ataxia was much improved.
AIDS Dementia Complex ; Brain ; Cerebellar Ataxia* ; Dementia ; Dysarthria ; Gait ; HIV Infections* ; HIV* ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; Neurologic Examination ; Neurologic Manifestations ; Pyramidal Tracts

BACKGROUND: The epidemiologic and clinical features of HIV infection/AIDS are different among various races, regions, and countries. To determine the epidemiologic and clinical characteristics of HIV infection in Korea, we analyzed and compared with that of other populations. METHODS: Medical records of 176 HIV-infected persons in Severance Hospital of Yonsei University College of Medicine and Hospital of Pusan University College of Medicine from year 1985 to 2000 were reviewed retrospectively. RESULTS: One hundred and seventy six patients were analyzed among which 156 (88.6%) were male and 20 (11.4%) were female with a male to female ratio of 7.8:1. At the time of diagnosis, the age distribution was 78 cases (44.3%) in the thirties, 44 cases (25.0%) in the twenties, and 35 cases (19.9%) in the fourties, and the mean age was 35.9+/-9.3. Heterosexual contact was the most frequent transmission route (92 cases, 52.3%), and 42 cases (23.9%) were transmitted by homosexual contact. At initial visit, asymptomatic HIV infection constituted 75 cases (42.6%), and AIDS 72 cases (40.9%). At initial visit, mean value of CD4+ lymphocyte counts was 252/mm3 and HIV RNA 226,035 copies/mm3. One hundred and twenty one of 176 patients developed 317 cases of opportunistic diseases. At the diagnosis of HIV-related opportunistic diseases, mean CD4+ lymphocyte count was 140/mm3 and mean HIV RNA 347,403 copies/mm3. Candidiasis (50 cases, 28.4%) was the most frequent opportunistic disease followed by pneumocystis carinii pneumonia (PCP) (37 cases, 21.0%), tuberculosis (29 cases, 16.5%), cytomegalovirus (CMV) infection (21 cases, 11.9%), HIV encephalopathy (9 cases, 5.1%), and herpes zoster (9 cases, 5.1%). There were 3 cases (1.7%) of malignant lymphoma and 2 cases (1.1%) of Kaposi's sarcoma. At the diagnosis of opportunistic diseases, mean CD4+ lymphocyte counts of patients with candidiasis was 71/mm3, PCP 63/mm3, and tuberculosis 142/mm3, and the mean HIV RNA level was 338,474 copies/mm3, 281,967 copies/mm3, and 817,012 copies/mm3 respectively. Among the 317 opportunistic diseases, AIDS-defining diseases were 150 cases (47.3%), of which PCP was 37 cases (24.7%), tuberculosis 29 cases (19.3%), CMV infection 21 cases (14.0%), HIV wasting syndrome 15 cases (10.0%), and esophageal candidiasis 14 cases (9.3%). The earliest AIDS-defining diseases to manifest in AIDS patients were tuberculosis (25 cases, 33.3%), followed by PCP (17 cases, 22.6%), esophageal candidiasis (14 cases, 18.7%), CMV infection (5 cases, 6.6%), and HIV wasting syndrome (4 cases, 5.3%). Thirty five (19.9%) of 176 patients were died. The common causes of death were tuberculosis (9 cases, 25.7%), PCP (9 cases, 25.7%), bacterial pneumonia (7 cases, 20.0%) and HIV encephalopathy (3 cases, 8.5%). CONCLUSION: The epidemiologic and clinical features of HIV infection/AIDS in Korea are different from that of developing countries such as Southeast Asia and Africa as well as from that of developed countries.
Africa ; Age Distribution ; AIDS Dementia Complex ; Asia, Southeastern ; Busan ; Candidiasis ; Cause of Death ; Continental Population Groups ; Cytomegalovirus ; Developed Countries ; Developing Countries ; Diagnosis ; Epidemiology ; Female ; Herpes Zoster ; Heterosexuality ; HIV Infections ; HIV Wasting Syndrome ; HIV* ; Homosexuality ; Humans ; Korea ; Lymphocyte Count ; Lymphoma ; Male ; Medical Records ; Pneumonia, Bacterial ; Pneumonia, Pneumocystis ; Retrospective Studies ; RNA ; Sarcoma, Kaposi ; Tuberculosis