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Distúrbios neurocognitivos associados à infeção por HIV - Patogénese e perspetivas de tratamento
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O desenvolvimento e implementação da terapêutica antirretroviral combinada (TARc) resultou na diminuição da taxa de mortalidade associada ao vírus da imunodeficiência humana (HIV), o que conduziu a um aumento significativo da esperança média de vida dos doentes HIV positivos. No entanto, os distúrbios neurocognitivos associados ao HIV (HAND) são ainda um problema observado nesta população, afetando a sua qualidade de vida. A designação HAND compreende um largo espectro de patologias que afetam o sistema nervoso central (SNC), que variam na sua gravidade e complexidade, desde o Comprometimento Neurocognitivo Assintomático (ANI), o Distúrbio Neurocognitivo Menor (MND) e a Demência Associada ao HIV (HAD). Nos períodos iniciais os doentes apresentam dificuldades de concentração, memória e alteração nas funções executivas, podendo progredir para estados de demência. Já nos doentes com ausência de terapêutica dirigida ao HIV ou com insucesso da mesma, a HAND caracteriza-se por encefalite ou leucoencefalite. O HIV acede ao SNC no início da infeção através de monócitos infetados que atravessam a barreira hemato encefálica (BHE), contudo não consegue infetar os neurónios, sendo a microglia e os macrófagos os principais alvos. A degeneração observada é resultado da produção de proteínas virais, principalmente a Tat e a gp120, e da libertação de citocinas próinflamatórias que geram uma inflamação causando lesão neuronal. No que diz respeito aos mecanismos de patogénese indiretos que conduzem à deterioração cognitiva consideram-se as infeções oportunistas típicas da infeção por HIV, neurotoxicidade associada à TARc, bem como alterações decorrentes do envelhecimento como Alzheimer e mais raramente demência com corpos de Lewy. A identificação de biomarcadores capazes de identificar lesões no SNC associadas ao vírus numa fase precoce da doença, irá permitir atuar de modo a diminuir a sintomatologia e proporcionar um controlo da doença. Diminuir os fatores de risco e identificar novas abordagens terapêuticas direcionadas ao SNC permanece um desafio. Quando superado permitirá aumentar a qualidade de vida assim como a sobrevivência destes doentes.
The development and implementation of combination antiretroviral therapy (cART) has resulted in a decrease in the human immunodeficiency virus (HIV) associated mortality rate, leading to a significant increase in the average life expectancy of HIV-positive patients. However, HIV-associated neurocognitive disorders (HAND) are still a problem observed in this population, affecting their quality of life. The HAND designation encompasses a broad spectrum of CNS diseases which may vary in severity and complexity, from Asymptomatic Neurocognitive Impairment (ANI), Minor Neurocognitive Disorder (MND), and HIVassociated Dementia (HAD). In the early periods, patients present difficulties in concentration, memory and changes in executive functions and may progress to dementia. In patients with or without HIV therapy, HAND is characterized by encephalitis or leukoencephalitis. HIV accesses the CNS at the beginning of infection through monocytes that cross the blood brain barrier (BBB), but cannot infect neurons, with microglia and macrophages being the main targets. The observed degeneration is a result of the production of viral proteins, mainly Tat and gp120, and the release of proinflammatory cytokines that generate inflammation causing neuronal damage. With regard to the indirect pathogenesis mechanisms leading to cognitive impairment, the typical opportunistic infections of HIV, cART-related neurotoxicity, as well as aging-related changes such as Alzheimer's and more rarely dementia with Lewy bodies are considered. The identification of biomarkers capable of recognozing virus-associated lesions in CNS at an early stage of the disease will allow an early intervation in such way that will diminish symptoms and allow a disease control. Reducing risk factors and identifying new therapeutic approaches aimed to CNS remains a challenge. When overcomed it may increse the quality of life and survival of these patients.
The development and implementation of combination antiretroviral therapy (cART) has resulted in a decrease in the human immunodeficiency virus (HIV) associated mortality rate, leading to a significant increase in the average life expectancy of HIV-positive patients. However, HIV-associated neurocognitive disorders (HAND) are still a problem observed in this population, affecting their quality of life. The HAND designation encompasses a broad spectrum of CNS diseases which may vary in severity and complexity, from Asymptomatic Neurocognitive Impairment (ANI), Minor Neurocognitive Disorder (MND), and HIVassociated Dementia (HAD). In the early periods, patients present difficulties in concentration, memory and changes in executive functions and may progress to dementia. In patients with or without HIV therapy, HAND is characterized by encephalitis or leukoencephalitis. HIV accesses the CNS at the beginning of infection through monocytes that cross the blood brain barrier (BBB), but cannot infect neurons, with microglia and macrophages being the main targets. The observed degeneration is a result of the production of viral proteins, mainly Tat and gp120, and the release of proinflammatory cytokines that generate inflammation causing neuronal damage. With regard to the indirect pathogenesis mechanisms leading to cognitive impairment, the typical opportunistic infections of HIV, cART-related neurotoxicity, as well as aging-related changes such as Alzheimer's and more rarely dementia with Lewy bodies are considered. The identification of biomarkers capable of recognozing virus-associated lesions in CNS at an early stage of the disease will allow an early intervation in such way that will diminish symptoms and allow a disease control. Reducing risk factors and identifying new therapeutic approaches aimed to CNS remains a challenge. When overcomed it may increse the quality of life and survival of these patients.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2019
Palavras-chave
Vírus da imunodeficiência humana (HIV-1) Distúrbios neurocognitivos Neuroinflamação Proteínas virais Terapêutica antirretroviral combinada (TARc) Mestrado Integrado - 2019