Altered T cell homeostasis during HIV-1 infection : consequences of lymphopenia and chronic T cell activation
Despite all the intense efforts and important progress achieved worldwide by the scientific community and public-health organizations, the HIV pandemic remains without effective solutions. The pathogenic mechanisms underlying the immunodeficiency that follows HIV-1 infection are still poorly understood. This lack of understanding is likely the main reason why at present there is neither a cure nor a vaccine for HIV-1 infection. In this thesis I address two main aspects of the pathogenesis of HIV-1 infection 1) the enhancement of T cell sensitivity to apoptotic and proliferative signals during lymphopenic conditions and 2) the role of chronic T cell activation in the generation of terminally differentiated T cells that might further contribute to the exacerbation of immune activation observed during HIV-1 infection.
In paper I we showed that IL-7, a cytokine that was primarily associated with anti-apoptotic and proliferative effects of T lymphocytes, can potently induce Fas expression on T cells. This implied also an increased sensitivity to Fas mediated apoptosis. The correlation found between serum levels of IL-7, Fas expression and sensitivity to Fas mediated apoptosis exhibited by T cells from HIV-1 infected individuals strongly indicated a role for IL-7 in the enhanced sensitivity of T cells to Fas-mediated apoptosis observed during HIV-1 infection.
In paper II, we demonstrate that Fas, previously associated to cell death, can act as a potent co-stimulatory molecule during HIV-1 infection. Of relevance is that the rates of proliferation greatly exceeded the levels of apoptosis upon Fas signals. Moreover, we demonstrate that IL-7 primes T cells to Fas co-stimulatory signals. Hence, the high levels of serum IL-7 associated with HIV-1 infection may enhance the sensitivity of non-activated T cells to Fas mediated apoptosis, while in the case of T cells able to recognize low affinity antigens it might enhance Fas-mediated proliferation.
In Paper III, we studied the phenotypic and functional characteristics of CD28- T lymphocytes from both healthy and HIV-1 infected individuals treated with HAART or naïve to treatment. We show that these cells exhibit certain characteristics of senescence and an apoptosis prone phenotype, independently if they originated from healthy or HIV-1 infected individuals. Interestingly, only CD28- T cells from untreated patients showed high levels of apoptosis upon TCR triggering whereas the CD28- T cells from patients undergoing HAART exhibited a strong proliferative response. Our findings suggest viral replication as an important factor regulating the homeostasis of CD28- T cells.
In Paper IV we show that naturally occurring CD28- cells, either from healthy or HIV-1 infected individuals, contributed to enhance DC activation. This paper provides evidence for a role of CD28- T cell population in the accelerated inflammatory reactions and immune activation through promoting the production of inflammatory cytokines by DCs.
In summary, the work presented in this thesis, possibly provides further insights into the pathogenesis of HIV-1 infection, characterized by a vicious circle formed between lymphopenia-induced rescue mechanisms and chronic immune activation, main inducers of immunodeficiency through the alteration of T cell homeostasis.
List of scientific papers
I. Fluur C, De Milito A, Fry TJ, Vivar N, Eidsmo L, Atlas A, Federici C, Matarrese P, Logozzi M, Rajnavölgyi E, Mackall CL, Fais S, Chiodi F, Rethi B. (2007). "Potential role for IL-7 in Fas-mediated T cell apoptosis during HIV infection." J Immunol. 178(8): 5340-50
https://pubmed.ncbi.nlm.nih.gov/17404319
II. Rethi B, Vivar N, Sammicheli S, Fluur C, Ruffin N, Atlas A, Rajnavolgyi E, Chiodi F. (2008). "Priming of T cells to Fas-mediated proliferative signals by interleukin-7. Blood." Blood 112(4): 1195-204
https://pubmed.ncbi.nlm.nih.gov/18441236
III. Vivar N, Ruffin N, Sammicheli S, Hejdeman B, Rethi B, Chiodi F (1970). "Survival and proliferation of CD28- T cells in HIV-1 infection is determined by the levels of HIV-1 replication." (Manuscript)
IV. Vivar N, Thang PH, Atlas A, Chiodi F, Rethi B. (2008). "Potential role of CD8+CD28- T lymphocytes in immune activation during HIV-1 infection." AIDS 22(9): 1083-6
https://pubmed.ncbi.nlm.nih.gov/18520354
History
Defence date
2009-05-29Department
- Department of Microbiology, Tumor and Cell Biology
Publication year
2009Thesis type
- Doctoral thesis
ISBN
978-91-7409-395-7Number of supporting papers
4Language
- eng