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

Humans ; AIDS Dementia Complex/pathology* ; HIV Infections

We report a 33-year-old man with AIDS dementia complex, which is one of the most common neurologic complica-tion of HIV-1 infection. The man presented with mild psychomotor slowing and episodic loss of consciousness about 5 years after the detection of the HIV-1 infection. His symptoms included forgetfulness, concentration difficulties, apathy, and psychomotor retardation which progressed rapidly evolving into the characteristic features of terminal HIV-1-asso-ciated dementia complex, such as severe dementia, mutism, incontinence, and paraparesis before death. Brain MRIrevealed diffuse confluent high signal intensity lesions in the subcortical white matter on the T2 weighted image. HIV encephalitis (AIDS dementia complex) was confirmed by a brain autopsy.
Acquired Immunodeficiency Syndrome ; Adult ; AIDS Dementia Complex* ; Apathy ; Autopsy* ; Brain ; Dementia ; Encephalitis ; HIV ; HIV-1 ; Humans ; Mutism ; Paraparesis ; Unconsciousness

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

Immunological mechanisms involving the release of inflammatory factors by HIV-1 infected microglia in the brain have been implicated in the pathogenesis of HIV dementia (HIVD). Since the regulation of matrix metalloproteinases (MMPs) activity can be influenced by variety of inflammatory mediators, this study was undertaken to look for a correlation between the MMP-9 release and the production of TNF-alpha in response to HIV-1 p24 in the human monocyte cell line THP-1 as a model for microglia. First, it was shown that HIV-1 core p24 antigen induced THP-1 to secrete MMP-9 in a dose response manner while it elicited a little effect on MMP-2 release in human astroglial cell line T98G. Next, it was found that p24 induced THP-1 to secrete TNF-alpha without prior differentiation into macrophages by phorbol myristate acetate (PMA) treatment. Furthermore, anti-TNF-alpha neutralizing antibodies significantly blocked p24-induced MMP-9 release in a dose dependent manner. Our data indicate that p24 antigen induces monocytic MMP-9 release by triggering up-regulation of TNF-alpha secretion.
AIDS Dementia Complex ; Antibodies, Neutralizing ; Brain ; Cell Line* ; HIV-1* ; Humans* ; Macrophages ; Matrix Metalloproteinase 9* ; Matrix Metalloproteinases ; Microglia ; Monocytes ; Tetradecanoylphorbol Acetate ; Tumor Necrosis Factor-alpha* ; Up-Regulation

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

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

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

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