A imunologia da infecção pelo HIV em pacientes com idade avançada: caracterização fenotípica e funcional da resposta imune mediada pela célula T CD4+

Abstract

The proportion of aged persons living with the acquired immunodeficiency syndrome (aids) has importantly increased in recent years and, up to the present moment, there are few studies that address the infection in this particular population. The immunological nuances resulting from the immunosenescence phenomenon may promote significant alterations in the clinical course of HIV infection, as well as in treatment response. The major purpose of this Thesis was to evaluate the impact of age on the functional immune recovery in aids patients aged more than 55 years, when adequately treated with anti-retroviral therapy, characterizing the immunological result of advanced age and HIV infection. Thus, four experimental groups were enrolled: healthy or HIV-infected young adults, and healthy or HIV-infected adults over 55 years old. All the HIV-infected patients had diagnosis of aids and were under anti-retroviral treatment with therapeutic success. In the first presented article, we evaluated the lymphoproliferative response and cytokine production in vitro and humoral response in vivo, after antigenic challenge with tetanus toxoid (TT) in previously immunized individuals against tetanus. The results revealed significant age-related immunological impairments concerning anti-TT IgG production, lymphoproliferative response and production of IFN-γ. On the other hand, the production of IL-10 significantly higher in individuals aged more the 55 years, HIV-infected or not. In the second article, T cell subsets were characterized after polyclonal activation or specific stimulus with antigens derived from the HIV envelope (Env). In fresh unstimulated PBMC cultures obtained from the aged aids patients, there was a reduced frequency of naïve and central memory T cells, associated with increased frequency of effector T cells. When polyclonally stimulated, these cultures showed deficient production of IFN-γ and hyperproduction of IL-10, like in response to TT. In Env-stimulated cultures, flow cytometry revealed high frequency of T CD4+FoxP3-CD152+ T cells with strong intracellular staining for IL-10, indicating a dominant Tr-1 phenotype, and not the classical Treg cells. Interestingly, in both articles, the viral replication in vitro was significantly lower aids patients over 55 years old, which is in consonance with their excellent virological response to anti-retroviral treatment. IL-10 neutralization with anti-IL-10 antibody in Env-activated cultures enhanced the viral replication in culture supernantants. Both in TT and in Env-peptides-stimulated cultures, the IL-10 blockade enhanced the levels of pro-inflammatory cytokines, but it did not improve IFN-γ production from aged aids patients. Altogether, the results reported in this Thesis reveal disturbances in several segments of the immune response, particularly in the Th1 compartment, of anti-retroviral-treated aids patients older than 55 years, suggesting that, for these patients, immune reconstitution after treatment does not occur with the same efficacy as in young patients. And although the enhanced IL-10 production probably contributes, at least in part, to the virological control, it can compromise the immune response both to HIV and to other antigenic challenges, such as tetanus toxoid. It is suggested, therefore, the need for specific recommendations regarding the clinical management of these patients