ALTERED T CELL HOMEOSTASIS DURING HIV-1 INFECTION : CONSEQUENCES OF LYMPHOPENIA AND CHRONIC T CELL ACTIVATION

Field: Medicine (Health Sciences)

Despite all the intense efforts and important progress achieved worldwide \nby the scientific community and public-health organizations, the HIV \npandemic remains without effective solutions. The pathogenic mechanisms \nunderlying the immunodeficiency that follows HIV-1 infection are still \npoorly understood. This lack of understanding is likely the main reason \nwhy at present there is neither a cure nor a vaccine for HIV-1 infection. \nIn this thesis I address two main aspects of the pathogenesis of HIV-1 \ninfection 1) the enhancement of T cell sensitivity to apoptotic and \nproliferative signals during lymphopenic conditions and 2) the role of \nchronic T cell activation in the generation of terminally differentiated \nT cells that might further contribute to the exacerbation of immune \nactivation observed during HIV-1 infection. \n \n \n \nIn paper I we showed that \nIL-7, a cytokine that was primarily associated with anti-apoptotic and \nproliferative effects of T lymphocytes, can potently induce Fas \nexpression on T cells. This implied also an increased sensitivity to Fas \nmediated apoptosis. The correlation found between serum levels of IL-7, \nFas expression and sensitivity to Fas mediated apoptosis exhibited by T \ncells from HIV-1 infected individuals strongly indicated a role for IL-7 \nin the enhanced sensitivity of T cells to Fas-mediated apoptosis observed \nduring HIV-1 infection. \n \n \n \nIn paper II, we demonstrate that Fas, previously \nassociated to cell death, can act as a potent co-stimulatory molecule \nduring HIV-1 infection. Of relevance is that the rates of proliferation \ngreatly exceeded the levels of apoptosis upon Fas signals. Moreover, we \ndemonstrate that IL-7 primes T cells to Fas co-stimulatory signals. \nHence, the high levels of serum IL-7 associated with HIV-1 infection may \nenhance the sensitivity of non-activated T cells to Fas mediated \napoptosis, while in the case of T cells able to recognize low affinity \nantigens it might enhance Fas-mediated proliferation. \n \n \n \nIn Paper III, we \nstudied the phenotypic and functional characteristics of CD28- T \nlymphocytes from both healthy and HIV-1 infected individuals treated with \nHAART or naïve to treatment. We show that these cells exhibit certain \ncharacteristics of senescence and an apoptosis prone phenotype, \nindependently if they originated from healthy or HIV-1 infected \nindividuals. Interestingly, only CD28- T cells from untreated patients \nshowed high levels of apoptosis upon TCR triggering whereas the CD28- T \ncells from patients undergoing HAART exhibited a strong proliferative \nresponse. Our findings suggest viral replication as an important factor \nregulating the homeostasis of CD28- T cells. \n \n \n \nIn Paper IV we show that \nnaturally occurring CD28- cells, either from healthy or HIV-1 infected \nindividuals, contributed to enhance DC activation. This paper provides \nevidence for a role of CD28- T cell population in the accelerated \ninflammatory reactions and immune activation through promoting the \nproduction of inflammatory cytokines by DCs. \n \n \n \nIn summary, the work \npresented in this thesis, possibly provides further insights into the \npathogenesis of HIV-1 infection, characterized by a vicious circle formed \nbetween lymphopenia-induced rescue mechanisms and chronic immune \nactivation, main inducers of immunodeficiency through the alteration of T \ncell homeostasis.