Inflamación y neuropatogenia asociada al VIH / Inflammation and HIV-neuropatogenicity

La infección cerebral por el VIH puede resultar en una profunda afectación del conocimiento, comportamiento y capacidades motoras, todo ello conocido como complejo demencia sida (CDS) en adultos y encefalopatía en niños (EP). Aunque la introducción de la TARGA ha prolongado y mejorado la vida de los individuos infectados, parece claro que la terapia antirretroviral no proporcional una protección completa frente al daño neurológico observado en esta enfermedad. La demencia-VIH es un complejo fenómeno que aparece como resultado de varios mecanismos causados por múltiples mediadores utilizando diferentes vías de señalización intracelular. Ya que el VIH no parece infectar masivamente a las neuronas, el daño neuronal es probablemente inducido por factores solubles entre los que se incluyen proteínas virales (gp120 y Tat principalmente), citocinas proinflamatorias, quimiocinas y prostaglandinas liberadas por macrófagos cerebrales infectados y células de la microglía activadas y/o infectadas. Estos factores solubles son además los responsables de la activación de células no infectadas aumentando y perpetuando de este modo el daño cerebral. Es pues necesario que la terapia esté dirigida no solo a limitar la infección de la microglía sino también la producción de estos mediadores inflamatorios y la activación de los astrocitos, para poder disminuir el daño neuronal observado en esta enfermedad (AU)

Brain HIV-1-infection may result in a syndrome of profound cognitive, behavioural and motor impairment known as AIDS dementia complex (ADC) in adults and HIV-related encephalopathy in children. Although the introduction of HAART has prolonged and improved the lives of infected individuals, it is clear that HAART does not provide complete protection against neurological damage in HIV/AIDS. HIV- 1associated dementia is a complex phenomenon, which could be the result of several mechanisms caused by those players using different intracellular signalling pathways. Since HIV-1 does not easily infect neuronal cells, neuronal damage is likely to be induced by soluble factors including viral proteins, proinflammatory cytokines, chemokines or prostaglandins released by HIV-1-infected macrophages or microglial cells. These soluble factors are also responsible for activation of uninfected cells and, thus, for spreading and perpetuation of brain damage. Thus, it is necessary an antiretroviral therapy that not only inhibit microglia infection, but also diminish proinflammatory factors and astrocytic activation to reduce neuronal damage (AU)

Effects of polymorphisms of chemokine receptors on neurodevelopment and the onset of encephalopathy in children with perinatal HIV-1 infection.

This study examined the effects of chemokine receptor polymorphisms on neurodevelopment and the onset of encephalopathy in children with perinatal HIV-1 infection. Infected children (N = 121) between the ages of I and 72 months were categorized into dichotomous groups (heterozygous or homozygous mutant vs. homozygous wild type) for each chemokine receptor 2 (CCR2) and chemokine receptor 5 (CCR5) allele. Neurodevelopmental measures included the Bayley Scales of Infant Development (BSID)for children age < or = 30 months and the McCarthy Scales of Children's Abilities (MSCA) for children aged > 30 months. A basic linear spline was used to model the mean value at each visit for the relevant test index, with determination of the slope between 4-12 months, 12-30 months, and 31-72 months of age. A mixed model analysis of variance was used to compare differences between slopes (AP) and intercepts (AX) according to the presence or absence of the specified CCR2 or CCR5 polymorphism. Survival analyses were used to compare the onset of encephalopathy by chemokine receptor allelic grouping. After adjusting for potential confounds, statistically significant differences emerged in CCR5-39353, 39356, and 39402. Although the protective effects appeared to be discrete and transient, children with mutant CCR5 genotypes exhibited better neurodevelopmental outcomes than children with the wild type alleles. Chemokine polymorphisms did not appear to impact the onset of encephalopathy. Although possibly a temporary effect, HIV-1 infected children with selected mutant chemokine receptor polymorphims CCR5-39353, 39356, and 39402 may exhibit better neurodevelopmental outcome than children with the wild type allele.

Cognitive and motor deficits associated with HIV-2(287) infection in infant pigtailed macaques: a nonhuman primate model of pediatric neuro-AIDS.

Lentivirus-infected nonhuman primates exhibit behavioral and neurological pathology similar to human immunodeficiency virus (HIV)-infected humans and offer a means to examine the effects of lentivirus infection while controlling for confounding factors inherent in human populations. The purpose of this study was to examine cognitive and motor development in infant macaques vertically infected with HIV-2287. Subjects were 20 infant pigtail macaques (Macaca nemestrina); 8 controls born to uninfected dams, and 12 infants whose dams had been inoculated and infected with HIV-2287 in the third trimester of pregnancy. Eight of these pregnancies had undergone surgical procedures in the form of maternal amniotic catheters or maternal amniotic and fetal carotid artery and jugular vein catheters. Data indicated that catheterization had little or no impact on behavioral development. Seven infants were vertically infected (as measured by polymerase chain reaction (PCR) at birth) and five were not infected (as measured by PCR and coculture on repeated testing). Infected infants attained cognitive and motor milestones at significantly later ages than controls. Uninfected infants, born to infected dams, attained developmental milestones at later ages than controls on all tasks, but this reached statistical significance only for the Fine Motor Task. Attainment of milestones was not correlated with viral dose, maternal CD4+ levels at parturition or infant viral RNA levels at birth. Attainment of milestones was negatively correlated with infants' proportions of CD4+ lymphocytes at birth and significantly correlated with proportions of CD4+ lymphocytes 2 weeks after birth, indicating poorer performance in those infants with a more rapid CD4+ depletion. These cognitive and motor deficits closely resemble those observed in human infants and children infected with HIV and indicate that HIV-2287-infected infant macaques represent an excellent model of pediatric neuro-acquired immunodeficiency syndrome (neuroAIDS).

Neurodevelopmental/neuroradiologic recovery of a child infected with HIV after treatment with combination antiretroviral therapy using the HIV-specific protease inhibitor ritonavir.

BACKGROUND: Neurodevelopmental impairment has been identified in children infected with human immunodeficiency virus (HIV). The frequency and spectrum of neurologic impairment are greater in children than those reported for adults. In children, HIV is known to enter the central nervous system early in the course of the disease. The presentation of pediatric neuro-acquired immune deficiency syndrome ranges from static (eg, nonprogressive developmental delay) to progressive encephalopathy (eg, acquired microcephaly, pyramidal tract signs, and spasticity). It has been demonstrated that antiretroviral agents can improve or even reverse the course of neurologic impairment in children. These changes have been attributed to various degrees of central nervous system drug penetration. Increasingly, protease inhibitors and combination antiretroviral therapy using reverse transcriptase inhibitors are being used in the treatment of children infected with HIV. The addition of a protease inhibitor to nucleoside analogue therapy has been reported to delay disease progression and prolong life in adults with moderate to advanced HIV disease. No data currently exist on the impact of combination therapy using two nucleoside analogues and a protease inhibitor on neurodevelopmental and neurologic function in children with HIV infection. The following case report presents the effects of combination therapy using ritonavir in a child infected with HIV. CASE REPORT: An 8-year, 2-month-old African-American boy was infected with HIV through vertical transmission. Regular monitoring of the patient's neurodevelopmental status has been conducted as part of his participation in longitudinal research protocols. For the first 51/2 years of life, his neurodevelopmental status was normal, with cognitive functioning as measured by standardized psychometric tools solidly in the average range. Speech and language skills were age-appropriate. Tests of gross and fine motor functioning as well as evaluation of overall neurodevelopmental status suggested normal development. Magnetic resonance imaging (MRI) of the brain was consistently normal. His family reported that adaptive functioning, peer and family relationships, and behavior were all within normal limits. School reports indicated consistently that the patient was performing at age and grade level, with respect to both academic achievement and behavior. Initial concerns regarding the patient's development were expressed by both his family and school at age 6 years, 6 months. These concerns included difficulty with classroom work, decreased attention, word-finding problems, fatigue, staring spells, and loss of strength. His family and school reported a marked loss of skills acquired previously. Results of formal psychological and speech and language evaluation reflected statistically significant drops in test scores from baseline, with both delayed and atypical skills evident. The patient's condition worsened rapidly. Within a few months, he was no longer able to use sentences to communicate. Cognitive testing was attempted, but he was unable to participate because of significant fatigue, limited attention, and inability to communicate verbally. His family described periods of disorientation and confusion, lethargy, and disinterest in age-appropriate activities. He became agitated and overstimulated easily both in small group settings and in crowds. He demonstrated both fine and gross motor impairments. When frustrated, he displayed infantile and autistic-like behavior. MRI with contrast showed diffuse atrophy as well as mild prominence of the ventricles and sulcii compared with baseline assessment. In addition to fatigue and neurologic symptoms, wasting syndrome was diagnosed, with loss of percentiles in both weight and height by age 71/2 years. Low-grade elevation of liver function tests and amylase was noted. Blood cultures for mycobacteria were negative, as were serologic tests for hepatitis. (ABSTRACT TRUN

Microglia: a sensor to threats in the nervous system?

The parenchymal microglia are now believed to settle the CNS antenatally, being derived from a bone marrow precursor cell. Based on developmental and pathophysiological studies, at least four different types of parenchymal microglia can be distinguished: (i) the amoeboid microglia which are mainly found perinatally in white matter areas, such as the corpus callosum, i.e. the so-called "fountains of microglia", (ii) the ramified, resting microglia in the adult CNS, (iii) the activated, non-phagocytic microglia found in areas of secondary reaction due to nerve transection and (iv) the phagocytic microglia, found in areas of trauma, infection or neuronal necrosis. In addition, there are perivascular cells enclosed in the basal lamina which have a high turnover with a bone marrow precursor pool. While the function of resting microglia is still largely unknown, it is clear from observations in neuropathology that microglia are among the first cell types in the brain to respond to injuries. Their reaction pattern to injury has been termed a graded response, since the transformation of resting cells into phagocytes is under strict control in vivo. Microglial activation is a key cellular response in many infectious, inflammatory, traumatic, neoplastic, ischaemic and degenerative conditions in the CNS. In HIV encephalitis, the microglial involvement is striking, and approximately 25% of microglia contain viral DNA or RNA. Based on natural homing mechanisms with bone marrow precursor cells, HIV-infected monocytes/macrophages may home at an early stage to the CNS perivascular space and eventually spread the infection to resident microglia in the CNS which may be difficult to reach by pharmacological intervention. Further understanding of the mechanisms regulating microglial proliferation and activation in vivo may help to develop therapies targeting the potentially harmful microglial response in the injured CNS.

An AIDS training program for rural mental health providers.

A total of 194 mental health care providers in Arkansas, primarily from rural areas and small communities, participated in a four-hour training program designed to improve their knowledge about the psychosocial and neuropsychiatric aspects of HIV and AIDS. Participants' responses to questionnaires completed before and after training indicated that the program was successful in achieving its goal. However, only a minimal number of providers reported completing drug, alcohol, and sexual histories and AIDS risk assessments for any of their patients before the training occurred. The authors emphasize the importance of AIDS training for rural providers.

Neuropsychological impairment in human immunodeficiency virus-infection: implications for employment. HNRC Group. HIV Neurobehavioral Research Center.

Individuals infected with the human immunodeficiency virus-Type 1 (HIV-1), are at increased risk for neurobehavioral impairment, particularly in later stages of the disease. Even patients in the medically asymptomatic or minimally symptomatic stages of infection may show mild deficits on comprehensive neuropsychological (NP) test batteries, although the clinical significance of such deficits remains uncertain. The present study used vocational difficulties as markers of clinical significance of NP impairment. In a sample of 289 HIV-infected, nondemented men, those who evidenced NP impairment had a higher unemployment rate (p < .001) than did their unimpaired counterparts. In HIV-positive subjects who remained employed, NP impairment was strongly associated with subjective decreases in job-related abilities. Neither depression nor medical symptoms could explain the relationship between the NP impairment and employment problems. These results are consistent with previous studies investigating other neuropsychiatric disorders, which suggest that even mild NP impairment can interfere with employment status. From this standpoint, such impairment in HIV-infected persons may be described as "clinically significant."

[HIV infection in childhood]. / Die HIV-Infektion im Kindesalter.

The increasing heterosexual transmission of HIV leads to an increase of vertical HIV-infection from mother to child. In Austria 19 children below 13 years with AIDS are registered, 16 of them had been infected by their mothers (österreichische AIDS-Statistik, January 29, 1993). Clinical manifestations of HIV-infection in infants and children are different from those in adults. In this article we describe the typical signs like severe recurrent bacterial infections, failure to thrive, lymphoid interstitial pneumonia and neurologic symptoms as developmental delay, loss of previous acquired skills and progressive motor abnormalities. The difficulties of the diagnosis of HIV-infection in an infant born to a seropositive mother and problems with the integration of HIV-infected children in kindergarten and school are discussed.

Trends and survival for AIDS patients presenting with indicative neurologic diseases.

Nervous system involvement in patients with AIDS is frequent either due to direct infection by the HIV-1 or to opportunistic infections or neoplasms. In the present study we evaluate the epidemiologic characteristics of patients in whom the first AIDS manifestation was an indicative neurologic disease (IND) and the influence of such a presenting form in the patients' survival. Out of 1250 reported cases, 252 (20.2%) presented with one of the INDs, according with the CDC AIDS definition criteria. Neither sex nor age differences were found between patients presenting with and without an IND. IVDUs were more likely to present with an IND than homosexual/bisexual men (p = 0.024). Cerebral toxoplasmosis (CT) was the only IND with a significant proportional increase over time. Although some of the IND have a specific treatment, as a whole patients presenting with an IND lived shorter than those presenting with any of the other indicative disorders (p less than 0.0001). The incidence of IND is greater than elsewhere, mainly because of CT. The increment of CT may be in part due to the introduction of the new AIDS definition criteria.

Effect of the revised AIDS case definition on AIDS reporting in San Francisco: evidence of increased reporting in intravenous drug users.

To examine the effect of the revision of the US national AIDS case definition in September 1987, we compared demographic and clinical information for AIDS patients diagnosed and reported to the San Francisco Department of Public Health between 1 September 1987 and 31 October 1989. Of the 3167 patients diagnosed and reported during the study period, 584 (18%) met the revised case definition only, increasing AIDS case reporting in San Francisco by 23%. One hundred and thirty-four of these 584 patients (23%) subsequently developed diagnoses meeting the old definition. After adjusting for this proportion, the revised case definition increased reporting by 17%. The mean time between initial diagnosis with a disease meeting the revised definition and subsequent development of a disease meeting the old definition was 18.5 months. Patients who met the revised case definition only were slightly older and more likely to be Black, female, and intravenous drug users (IVDUs) than those meeting the old case definition. The majority of patients who met the revised case definition only had initial diagnoses of HIV wasting syndrome (26%), HIV encephalopathy (21%), and presumptive Pneumocystis carinii pneumonia (19%). The revised AIDS case definition has significantly increased the reporting of severe morbidity associated with HIV infection, particularly among IVDUs.