RESUMEN

OBJECTIVES: Growing evidence suggested that antiretroviral (ARV) drugs may promote amyloid beta (Aß) accumulation in HIV-1-infected brain and the persistence of HIV-associated neurocognitive disorders (HANDs). It has also been shown that lipid peroxidation upregulates ß-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) expression and subsequently promotes Aß peptide production. In the present study, we examined whether chronic exposure to the anti-HIV drugs tenofovir disoproxil fumarate (TDF) and nevirapine induces lipid peroxidation thereby promoting BACE1 and Aß generation and consequently impair cognitive function in mice. METHODS: TDF or nevirapine was orally administered to female BALB/c mice once a day for 8 weeks. On the 7th week of treatment, spatial learning and memory were assessed using the Morris water maze test. The levels of lipid peroxidation, BACE1, amyloid ß 1-42 (Aß1-42) and Aß deposits were measured in the hippocampal tissue upon completion of treatment. RESULTS: Chronic administration of nevirapine induced spatial learning and memory impairment in the Morris water maze test, whereas TDF did not have an effect. TDF and nevirapine administration increased hippocampal lipid peroxidation and Aß1-42 concentration. Nevirapine further upregulated BACE1 expression and Aß deposits. CONCLUSION: Our results suggest that chronic exposure to TDF and nevirapine contributes to hippocampal lipid peroxidation and Aß accumulation, respectively, as well as spatial learning and memory deficits in mice even in the absence of HIV infection. These findings further support a possible link between ARV drug toxicity, Aß accumulation and the persistence of HANDs.

Asunto(s)

Complejo SIDA Demencia/inducido químicamente , Péptidos beta-Amiloides/efectos de los fármacos , Fármacos Anti-VIH/farmacología , Infecciones por VIH/tratamiento farmacológico , Discapacidades para el Aprendizaje/inducido químicamente , Memoria/efectos de los fármacos , Administración Oral , Secretasas de la Proteína Precursora del Amiloide/efectos de los fármacos , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/efectos de los fármacos , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/toxicidad , Ácido Aspártico Endopeptidasas/efectos de los fármacos , Ácido Aspártico Endopeptidasas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/virología , Disfunción Cognitiva/inducido químicamente , Modelos Animales de Enfermedad , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Hipocampo/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Nevirapina/efectos adversos , Nevirapina/farmacología , Nevirapina/toxicidad , Tenofovir/efectos adversos , Tenofovir/farmacología , Tenofovir/toxicidad

RESUMEN

Although highly active antiretroviral therapy has led to improved prognosis and alleviation of some HIV-related disease complications, it has not provided complete protection against HIV-associated dementia. As the population of persons living with HIV grows older and aged persons represent a significant number of new infections, it is important to understand how HIV may affect the aged brain. In the current study, both adult and aged mice were treated with HIV gp120 and trained in a reference memory version of the water maze. Analysis of probe data revealed that aged animals treated with gp120 demonstrated profound decrements in water maze performance compared to gp120 treated young animals and saline treated aged or young animals. Additionally, we examined the neuroinflammatory responses in the aged and adult brain 4 h after treatment with gp120. Pro-inflammatory cytokines associated with neuroinflammation are known to be antagonistic to learning and memory processes and aged and adult animals treated with gp120 demonstrated similar increases in IL-1ß and IL-6 in the hippocampus and cortex. Additionally, gp120 treatment was associated with an increase in MHCII gene expression, a marker of microglial activation, in the hippocampus. Although, the aged brain demonstrated a similar inflammatory profile at the time point measured, aged animals were more sensitive to cognitive dysfunction related to gp120 treatment. This finding supports the theory that aging may be a significant risk factor in the development of HIV-associated dementia.

Asunto(s)

Complejo SIDA Demencia/fisiopatología , Envejecimiento/psicología , Proteína gp120 de Envoltorio del VIH/toxicidad , Complejo SIDA Demencia/inducido químicamente , Complejo SIDA Demencia/genética , Envejecimiento/genética , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Interleucina-1beta/biosíntesis , Interleucina-1beta/genética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones Endogámicos BALB C , ARN Mensajero/genética , Factores de Riesgo

RESUMEN

Investigators reported many new neuroHIV research findings at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI). These findings included confirmation that HIV-associated neurocognitive disorder (HAND) remains common with an increasingly recognized role for comorbidities (eg, obesity) and neurodegenerative conditions (eg, Alzheimer's disease), especially as persons living with HIV (PLWH) advance into their seventh decade of life and beyond. HAND is increasingly recognized as a heterogeneous disorder that differs between individuals (eg, by sex) in the trajectory of specific neurocognitive abilities (eg, executive functioning). A more recent focus at this year's conference was toxicity of combination antiretroviral therapy: neurocognitive performance and neuroimaging data from several studies were presented but did not consistently support that integrase strand transfer inhibitors are associated with worse neurologic outcomes. Neuroimaging studies found that white matter changes reflect a combination of the effects of HIV and comorbidities (including cerebrovascular small vessel disease) and best correlate with blood markers of inflammation. The pathogenesis of HIV in the central nervous system (CNS) was the focus of a plenary lecture and numerous presentations on HIV compartmentalization in the CNS and cerebrospinal fluid viral escape. Novel findings were also presented on associations between HIV-associated neurologic complications and glycomics, neuron-derived exosomes, and DNA methylation in monocytes. This summary will review findings from CROI and identify new research and clinical opportunities.

Asunto(s)

Complejo SIDA Demencia/patología , Complejo SIDA Demencia/fisiopatología , Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Complejo SIDA Demencia/inducido químicamente , Complejo SIDA Demencia/diagnóstico por imagen , Fármacos Anti-VIH/uso terapéutico , Comorbilidad , Humanos , Neuroimagen/métodos

RESUMEN

The application of combination antiretroviral therapy has greatly reduced the death rate from AIDS. However, up to 50% of patients on combination antiretroviral therapy develop HIV-associated neurocognitive disorders (HAND), which is associated with residual neuroinflammation and oxidative injury in the brain. Neural stem cells (NSCs) and progenitors play a vital role in repairing neuronal injuries. Therefore, we hypothesize that combination antiretroviral therapy may adversely affect NSCs/progenitors, contributing to the increasing prevalence of HAND. Here, we show that combined medication of three antiretroviral drugs tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and raltegravir (RAL) affects NSC homeostasis and progenitor proliferation in the mouse dentate gyrus (DG). Our results also show that TDF/FTC/RAL treatment prohibits proliferation and induces apoptosis of cultured mouse neural progenitor cells (NPCs), resulting in a reduction in the viability of NPCs. Moreover, we find that TDF, among the three drugs used in this combination antiretroviral treatment, accounts for most of the effects on neural progenitors. Together, our results offer a mechanistic explanation for the prevalence of HAND in AIDS patients treated with combination antiretroviral therapy.

Asunto(s)

Complejo SIDA Demencia/inducido químicamente , Fármacos Anti-VIH/toxicidad , Emtricitabina/toxicidad , Células-Madre Neurales/efectos de los fármacos , Raltegravir Potásico/toxicidad , Tenofovir/toxicidad , Animales , Terapia Antirretroviral Altamente Activa/efectos adversos , Proliferación Celular/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL

RESUMEN

Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70 % of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers.

Asunto(s)

Complejo SIDA Demencia/metabolismo , Dopamina/metabolismo , Infecciones por VIH/metabolismo , Macrófagos/metabolismo , Monocitos/metabolismo , Linfocitos T/metabolismo , Complejo SIDA Demencia/inducido químicamente , Complejo SIDA Demencia/inmunología , Animales , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Dopaminérgicos/farmacología , Dopaminérgicos/toxicidad , Infecciones por VIH/inmunología , Humanos , Drogas Ilícitas/farmacología , Drogas Ilícitas/toxicidad , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Monocitos/efectos de los fármacos , Monocitos/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología

RESUMEN

Our objective was to evaluate whether thrombocytopenia and small thymus volume, which may be associated with hazardous alcohol consumption, are predictors of cognitive performance after highly-active antiretroviral treatment (HAART). To achieve this goal 165 people living with HIV starting HAART underwent thymus magnetic resonance imaging, cognitive (HIV Dementia Score [HDS] and the California Verbal Learning Test [CVLT]), immune and laboratory assessments at baseline and after 6 months of HAART. At baseline, hazardous alcohol consumption was significantly correlated with both thymus size (r = -0.44, p = 0.003) and thrombocytopenia (r = 0.28, p = 0.001). Of interest, thrombocytopenic patients were characterized by a smaller thymus size. Individuals with and without cognitive impairment differed in alcohol consumption, platelet counts and thymus size, suggesting that they may be risk factors for neurological abnormalities. In fact, after HAART hazardous alcohol use associations with thrombocytopenia were related to cognitive decline (learning = -0.2 +/- 0.8, recall = -0.3 +/- 0.1 and HDS = -0.5). This contrasted with improvements on every cognitive measure (learning = 1.6 +/- 0.3, p = 0.0001, recall = 2.2 +/- 0.4, p = 0.0001 and HDS = 1.0, p = 0.05) in those with neither alcohol use nor thrombocytopenia. In adjusted analyses for sociodemographics, adherence and immune measurements, reduced thymus size was associated with a 90% and thrombocytopenia with a 70% increase in the risk of scoring in the demented range after HAART (RR = 1.9, p < 0.05 and RR = 1.7, p = 0.03) and with low CVLT scores (thymus volume RR = 2.0, p = 0.04, chronic alcohol use p = 0.05 and thrombocytopenia p = 0.06). Thymus volume and platelet counts were negatively affected by alcohol and were predictors of cognitive performance and improvements after HAART. These results could have important clinical and therapeutic implications.

Asunto(s)

Consumo de Bebidas Alcohólicas/efectos adversos , Plaquetas/efectos de los fármacos , Cognición/efectos de los fármacos , Etanol/farmacología , Infecciones por VIH/fisiopatología , Timo/efectos de los fármacos , Complejo SIDA Demencia/inducido químicamente , Complejo SIDA Demencia/etiología , Adulto , Terapia Antirretroviral Altamente Activa , Estudios de Casos y Controles , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/etiología , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos/efectos de los fármacos , Recuento de Plaquetas , Trombocitopenia/inducido químicamente , Trombocitopenia/etiología , Resultado del Tratamiento

RESUMEN

Human immunodeficiency virus (HIV)-infected individuals who abuse opiates show faster progression to AIDS, and enhanced incidence of HIV-1 encephalitis. Most opiates with abuse liability are preferential agonists for mu-opioid receptors (MORs), and MORs are expressed on both neurons and glia, including oligodendrocytes (OLs). Tat, gp120, and other viral toxins, cause neurotoxicity in vitro and/or when injected into brain, and co-exposure to opiates can augment HIV-1 protein-induced insults to both glial and neuronal populations. We examined the effects of HIV-1 Tat +/- opiate exposure on OL survival and differentiation. In vivo studies utilized transgenic mice expressing Tat(1-86) regulated by an inducible glial fibrillary acidic protein promoter. Although MBP levels were unchanged on immunoblots, certain structural and apoptotic indices were abnormal. After only 2 days of Tat induction, OLs showed an upregulation of active caspase-3 that was enhanced by morphine exposure. Tat also upregulated TUNEL staining, but only in the presence of morphine. Tat significantly reduced the length of processes in Golgi-Kopsch impregnated OLs. A greater proportion of cells exhibited diminished or aberrant cytoplasmic processes, especially when mice expressing Tat were co-exposed to morphine. Collectively, our data show that OLs in situ are extremely sensitive to effects of Tat +/- morphine, although it is not clear if immature OLs as well as differentiated OLs are targeted equally. Significant elevations in caspase-3 activity and TUNEL labeling, and evidence of increased degeneration/regeneration of OLs exposed to Tat +/- morphine suggest that toxicity toward OLs may be accompanied by heightened OL turnover.

Asunto(s)

Complejo SIDA Demencia/metabolismo , Enfermedades Desmielinizantes/virología , Morfina/toxicidad , Oligodendroglía/virología , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genética , Complejo SIDA Demencia/inducido químicamente , Complejo SIDA Demencia/virología , Analgésicos Opioides/toxicidad , Animales , Apoptosis/genética , Caspasa 3/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Forma de la Célula/efectos de los fármacos , Forma de la Célula/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Células Cultivadas , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/fisiopatología , Etiquetado Corte-Fin in Situ , Ratones , Ratones Transgénicos , Vaina de Mielina/metabolismo , Vaina de Mielina/virología , Oligodendroglía/efectos de los fármacos , Oligodendroglía/patología , Tinción con Nitrato de Plata , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/metabolismo

RESUMEN

AIM: To explore the effect and mechanisms of curcumin on learning and memory dysfunction induced by HIV-1 enveloped protein gp120. METHODS: The SD rats were treated with gp120 by intracerebroventricular (ICV) infusion imitating the HIV-1 associated dementia (HAD) animal model. Subsequently, we applied the water maze test to evaluate the effect of gp120 on the learning and memory dysfunction in rats. The SD rats were divided into six groups: control group, sham group, model group, low dose curcumin group, middle dose curcumin group and high dose curcumin group. Except control and sham group, the others four groups received slowly 5 microL/d gp120 which dissolved in artificial cerebrospinal fluid (ACSF) for 3 days. Since the fourth day, the rats of low, middle, high dose curcumin groups were treated with 50 mg/(kg.d), 100 mg/(kg.d), 200 mg/(kg.d) curcumin, respectively. The others groups were treated with redistilled water. The treatment lasted for 14 days. Subsequently, the water maze test and NMDA2BR immunohistochemical staining were applied to evaluate the effect of curcumin on the rats. RESULTS: The rats were treated with gp120 50 ng/d by ICV infusion for 3 days can imitate the HAD animal model. The Morris water maze (MWM) test showed that the rats in model group had longer escape latencies compared with those in control group (P<0.05) and that rats in low, middle, high dose curcumin groups had shorter escape latencies compared with those in model group (P<0.05), and low dose curcumin group was better than the other two groups (P<0.05). Immunohistochemical staining showed that the expressions of NMDA2BR in model group decreased compared with the control groups (P<0.01), while the expressions of NMDA2BR in low, middle and high dose curcumin groups increased compared with the model groups. CONCLUSION: The SD rats were treated with gp120 by ICV infusion imitating the HAD animal model. The curcumin can improve the learning and memory dysfunction induced by gp120, the mechanism may be related to against the downregulation the expression of NMDA2BR.

Asunto(s)

Curcumina/uso terapéutico , Proteína gp120 de Envoltorio del VIH/toxicidad , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Complejo SIDA Demencia/inducido químicamente , Complejo SIDA Demencia/tratamiento farmacológico , Complejo SIDA Demencia/patología , Animales , Femenino , Inmunohistoquímica , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo

RESUMEN

Clinical and preclinical evidence suggests that cocaine exposure hastens progression of the HIV disease process. An established active, euphoric dose of cocaine (20 mg/kg) was administered to SCID mice according to a regimen consistent with exposure to the drug by cocaine-abusing HIV-infected patients to determine the effects of cocaine on four previously established pathological characteristics of HIV encephalitis: cognitive deficits, fatigue, astrogliosis, and microgliosis. Mice were intracranially inoculated with either HIV-infected, or uninfected macrophages and then injected with either cocaine or saline in a 2 (Infection)x2 (Cocaine) factorial design. Cognition was assessed by acquisition and retention of a spatially cued learning task. Fatigue was assessed by monitoring motor activity following a 2 min forced swim. Mice were then sacrificed to determine the extent of astrogliosis and microgliosis in the four groups. Results indicated that in comparison to uninfected controls, HIV positive mice had increased astrogliosis and microgliosis, cognitive deficits, and recovered more slowly from fatigue. However, despite evidence that the cocaine exposure regimen activated the central nervous system and had long-term CNS effects, the drug did not alter the behavioral or the neuropathological deficits noted in HIV-infected SCID mice.

Asunto(s)

Complejo SIDA Demencia/inducido químicamente , Complejo SIDA Demencia/fisiopatología , Encéfalo/efectos de los fármacos , Trastornos Relacionados con Cocaína/complicaciones , Trastornos Relacionados con Cocaína/fisiopatología , Cocaína/efectos adversos , Complejo SIDA Demencia/patología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Astrocitos/virología , Encéfalo/patología , Encéfalo/fisiopatología , Enfermedad Crónica , Trastornos Relacionados con Cocaína/patología , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/fisiopatología , Trastornos del Conocimiento/virología , Modelos Animales de Enfermedad , Inhibidores de Captación de Dopamina/efectos adversos , Fatiga/inducido químicamente , Fatiga/fisiopatología , Fatiga/virología , Gliosis/inducido químicamente , Gliosis/fisiopatología , Gliosis/virología , Masculino , Ratones , Ratones SCID , Microglía/efectos de los fármacos , Microglía/patología , Microglía/virología

RESUMEN

gp120, the coat glycoprotein of HIV, can damage CNS neurons. This appears to mostly involve an indirect pathway in which gp120 infects microglia, triggering the release of cytokines and glutamatergic excitotoxins which then damage neurons. A well-characterized response of cells to insults is to mobilize the heat stress response, a defense that has a number of protective consequences. We tested the capacity of gp120, at a dose well-documented to be neurotoxic, to activate the heat shock response in cultures from cortex and hippocampus, two brain regions sensitive to the neurotoxic effects of gp120. We found that gp120 failed to induce expression of hsp70, hsp25 or hsp90 in cortical or hippocampal cultures, under conditions where induction can be demonstrated in response to other insults. The failure of gp120 to induce a heat shock response is significant because we subsequently demonstrated that such an induction would have been beneficial. Specifically, over expression of hsp70 with a herpes viral amplicon vector protected cultured hippocampal neurons from gp120 neurotoxicity.

Asunto(s)

Corteza Cerebral/efectos de los fármacos , Proteína gp120 de Envoltorio del VIH/toxicidad , Proteínas HSP70 de Choque Térmico/metabolismo , Hipocampo/efectos de los fármacos , Complejo SIDA Demencia/inducido químicamente , Animales , Supervivencia Celular , Células Cultivadas , Corteza Cerebral/metabolismo , Embrión de Mamíferos , Femenino , Expresión Génica/efectos de los fármacos , Ácido Glutámico/farmacología , Hipocampo/metabolismo , Calor , Immunoblotting/métodos , Técnicas para Inmunoenzimas/métodos , Infecciones , Embarazo , Ratas , Ratas Sprague-Dawley , Factores de Tiempo

RESUMEN

Efavirenz is a nonnucleoside reverse transcriptase inhibitor that can be given with other antiretroviral agents for the treatment of human immunodeficiency virus infection. A 47-year-old man with acquired immunodeficiency syndrome developed severe depression and suicidal ideation necessitating psychiatric hospitalization and antidepressant therapy. The symptoms occurred in temporal relation to the introduction of efavirenz into his highly active antiretroviral therapy regimen. Similar serious psychiatric adverse effects have been associated with this agent. Clinicians should monitor for central nervous system adverse effects in all patients taking efavirenz.

Asunto(s)

Complejo SIDA Demencia , Trastornos Mentales , Oxazinas/efectos adversos , Complejo SIDA Demencia/inducido químicamente , Complejo SIDA Demencia/psicología , Alquinos , Terapia Antirretroviral Altamente Activa/efectos adversos , Benzoxazinas , Ciclopropanos , Humanos , Masculino , Trastornos Mentales/inducido químicamente , Trastornos Mentales/psicología , Persona de Mediana Edad

RESUMEN

Between 20 and 30% of AIDS patients have neurological symptoms characterized by motor impairment, memory loss and progressive dementia. Previous studies have implicated the HIV derived gp120, which produces behavioral deficits and electrophysiological alterations in rats. The goal of the present study was to describe the effect of this protein on the P3 event-related potential (ERP), evoked by a passive discrimination task in rats. We used II rats divided into two groups: HIV gp120 (n = 6) and control (n = 5). We recorded the P3 wave before any treatment (baseline), during the i.c.v. administration of either HIVgp 120 (700 ng/5 days) or saline (pH 7.2), and 24 h, 7, 14 and 21 days after the last injection. There were no changes between groups in the amplitude or latencies of the observed components (N1, P2, N2 and P3) evoked by target stimuli, during baseline or during the injection period. However, the HIV gp120 group showed a significant amplitude reduction in P3 wave 24 h after the last injection, while the N1, P2 and N2 waves remained unchanged. However, from the 7th day through the 21st day, P2 and N2 components also disappeared and only the N1 component could be observed in the HIV gp 20-treated group. These changes in the N2, P2 and P3 potentials, suggesting an alteration in cognitive processes, further support the neurotoxic activity of HIV gp120 and its role in AIDS dementia.

Asunto(s)

Complejo SIDA Demencia/fisiopatología , Aprendizaje Discriminativo/efectos de los fármacos , Potenciales Evocados/efectos de los fármacos , Proteína gp120 de Envoltorio del VIH/farmacología , Complejo SIDA Demencia/inducido químicamente , Estimulación Acústica , Animales , Conducta Animal/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Potenciales Evocados/fisiología , Potenciales Evocados Auditivos del Tronco Encefálico/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos

RESUMEN

Of the individuals with human immunodeficiency virus type 1 (HIV-1) infection, 20-30% will develop the neurological complication of HIV-associated dementia (HAD). The mechanisms underlying HAD are unknown; however, indirect immunologically mediated mechanisms are theorized to play a role. Recently, the HIV-1 coat protein gp41 has been implicated as a major mediator of HAD through induction of neurocytokines and subsequent neuronal cell death. Using primary mixed cortical cultures from neuronal nitric oxide synthase (NOS) null (nNOS-/-) mice and immunological NOS null (iNOS-/-) mice, we establish iNOS-derived NO as a major mediator of gp41 neurotoxicity. Neurotoxicity elicited by gp41 is markedly attenuated in iNOS-/- cultures compared with wild-type and nNOS-/- cultures. The NOS inhibitor L-nitroarginine methyl ester is neuroprotective in wild-type and nNOS-/- cultures, confirming the role of iNOS-derived NO in gp41 neurotoxicity. Confirming that iNOS-/- cultures lack iNOS, gp41 did not induce iNOS in iNOS-/- cultures, but it markedly induced iNOS in wild-type and nNOS-/- cultures. We elucidate the region of gp41 that is critical for iNOS induction and neuronal cell death by monitoring iNOS induction with overlapping peptides spanning gp41. We show that the N-terminal region of gp41, which we designate as the neurotoxic domain, induces iNOS protein activity and iNOS-dependent neurotoxicity at picomolar concentrations in a manner similar to recombinant gp41 protein. Our experiments suggest that gp41 is eliciting the induction of iNOS through potential cell surface receptors or binding sites because the induction of iNOS is dose dependent and saturable and occurs at physiologically relevant concentrations. These data confirm that the induction of iNOS by gp41 and the production of NO are primary mediators of neuronal damage and identify a neurotoxic domain of gp41 that may play an important role in HAD.

Asunto(s)

Complejo SIDA Demencia/inducido químicamente , Proteína gp41 de Envoltorio del VIH/toxicidad , Neuronas/efectos de los fármacos , Óxido Nítrico Sintasa/metabolismo , Estructura Terciaria de Proteína , Secuencia de Aminoácidos , Animales , Células Cultivadas , Progresión de la Enfermedad , Inhibidores Enzimáticos/farmacología , Mapeo Epitopo , Proteína gp41 de Envoltorio del VIH/química , Ratones , Datos de Secuencia Molecular , Neuronas/enzimología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo II

RESUMEN

In a pilot open-labeled study 10 subjects with AIDS dementia complex (ADC) were treated with didanosine. Only half of the subjects were able to complete the trial as a result of side effects. Five subjects exhibited improved performance on neuropsychological testing, but the mean change in performance in this small group was not statistically significant. The study suggests that this drug may have some value in ADC patients unable to tolerate other therapies, but that further study is needed to establish this firmly.

Asunto(s)

Complejo SIDA Demencia , Didanosina , Complejo SIDA Demencia/inducido químicamente , Humanos , Pruebas Neuropsicológicas , Proyectos Piloto