Fenótipos de não progressor e controlador na infecção por HIV

Trabalho final de mestrado integrado em Medicina área científica de Doenças Infecciosas, apresentado á Faculdade de Medicina da Universidade de CoimbraA infecção pelos Vírus da Imunodeficiência Humana (VIH) é caracterizada por um estado de replicação vírica crónico e por mecanismos de escape virais que impedem a sua irradicação. A progressão da infecção está marcada por um decréscimo progressivo das contagens de linfócitos T CD4+ e aumento concomitante das cargas víricas séricas. Não tratadas, o destino inexorável da maioria destas infecções é a progressão até ao seu estadio final, a Síndrome da Imunodeficiência Adquirida. Alguns doentes apresentam, no entanto, características de protecção à progressão. São chamados de “não progressores” ou “controladores”, de acordo com a sua característica de manutenção das contagens de linfócitos T CD4+ ou de controlo das cargas víricas no decurso da infecção, respectivamente, e estão associados a uma fase crónica assintomática de maior duração. Nestes doentes, os vírus colonizadores apresentam tipicamente uma redução da capacidade de replicação, determinada por deleções genéticas ou mutações de escape a uma pressão imunitária forte, e vários polimorfismos dos genes virais têm sido encontrados. Os “não progressores” e “controladores” aparentam ainda ter vantagens genéticas, nomeadamente a expressão de polimorfismos para os receptores celulares do vírus (como o Δ32 para o CCR5), ou uma maior produção de citocinas que competem pelos receptores celulares. Em termos imunológicos estes fenótipos são acompanhados de diversos achados. A imunidade inata aparenta ser mais precoce e mais eficiente, podendo permitir o desenvolvimento da imunidade adquirida em níveis suficientes para uma posterior resposta de controlo efectiva. As respostas celulares são na realidade mais polifuncionais e potentes, e estão correlacionadas com diversos factores, um dos mais importantes sendo a expressão de moléculas HLA de classe I que aparentam ter características protectoras Diversos factores têm sido pois implicados para este estado, e a mimetização dessas condições noutros doentes infectados propõe-se como uma efectiva medida de tratamento no futuro. A infecção por VIH é, após cerca de 30 anos de conhecimento, um dos maiores desafios com que nos deparamos na actualidade e o desenvolvimento de novas estratégias terapêuticas são necessárias para o controlo da progressão da pandemia existenteHuman Immunodeficiency Virus infection characterizes itself by a chronic state of viral replication and viral escape mechanisms, leading to difficult eradication. The infection progresses with a marked decrease of CD4+ cell counts and increasing viral loads, and, non-treated, the majority of infections progresses to its final step of AIDS. Some patients, however, present with protective characteristics to progression. They are generally called “nonprogressors” or “controllers”, according to their CD4+ cell count maintenance or of control of viral load during the course of infection, respectively, and are associated with a longer asymptomatic phase of the infection. In this particular group of patients, colonizing virus seems to present a diminished viral fitness, derived from original genetic deletions, or escape mutations to a strong host immune response, and several viral genetic polymorphisms have been found. Nonprogressors and controllers also seem to present with genetic advantages, namely the presence of polymorphisms to the cell surface receptors needed to viral entry, such as Δ32 to the CCR5 receptor, or a greater inhibitory cytokine production. As for the immunological system, this has been associated with many findings. Innate immunity appears as a faster and stronger response to an initiating infection, and thus may allow adaptive immunity to derive an effective controller response to the infection. An effective, polyfunctional and more powerful cell immunity is a concurrent finding and is associated with many immunological factors, a major one being protective HLA-I alleles expression. Diverse factors have as such been associated with this state, and there has been interest in understanding their possible role as contributors to a future treatment strategy in other infected patients.Human Immunodeficiency Virus infection characterizes itself by a chronic state of viral replication and viral escape mechanisms, leading to difficult eradication. The infection progresses with a marked decrease of CD4+ cell counts and increasing viral loads, and, non-treated, the majority of infections progresses to its final step of AIDS. Some patients, however, present with protective characteristics to progression. They are generally called “nonprogressors” or “controllers”, according to their CD4+ cell count maintenance or of control of viral load during the course of infection, respectively, and are associated with a longer asymptomatic phase of the infection. In this particular group of patients, colonizing virus seems to present a diminished viral fitness, derived from original genetic deletions, or escape mutations to a strong host immune response, and several viral genetic polymorphisms have been found. Nonprogressors and controllers also seem to present with genetic advantages, namely the presence of polymorphisms to the cell surface receptors needed to viral entry, such as Δ32 to the CCR5 receptor, or a greater inhibitory cytokine production. As for the immunological system, this has been associated with many findings. Innate immunity appears as a faster and stronger response to an initiating infection, and thus may allow adaptive immunity to derive an effective controller response to the infection. An effective, polyfunctional and more powerful cell immunity is a concurrent finding and is associated with many immunological factors, a major one being protective HLA-I alleles expression. Diverse factors have as such been associated with this state, and there has been interest in understanding their possible role as contributors to a future treatment strategy in other infected patients. HIV-1 infection is, after 30 years of research, an intensively developing field of knowledge and one of the great challenges of mankind. A new treatment strategy is paramount to controlling the progression of the existent global pandemi