Mechanism of CD8 T cell-mediated control of HIV-1 infection in HIV controllers

Abstract

[한글]

[영문]

"HIV controllers (HICs)” are a rare group of HIV infected individuals who have a spontaneous and durable control of the virus at an undetectable level without antiretroviral treatment. Understanding the mechanism of HIV-1 control in these individuals could give us a valuable scientific background in developing novel vaccine strategies and immune therapies. This spontaneous viral control in HICs is usually associated to strong and functional HIV-specific CD8+ T cell responses. It has been recently published that ex vivo CD8+ T cells from HICs were able to efficiently suppress HIV-1 infection in autologous CD4+ T cells, suggesting a central role of CD8+ T cell responses in the control of HIV-1 infection in vivo. To further characterize the HIV suppressive capacity of CD8+ T cells in HICs, the study has been extended investigating 19 HICs. Most of the HICs showed strong HIV suppressive capacity by ex vivo CD8+ T cells (strong responder HICs) confirming the previous results published. Suppressive capacity in strong responder HICs was stable over time and broad. Importantly, the CD8+ T cell mediated suppressive capacity in HICs correlated strongly with the frequency of Gag-specific CD8+ T cells. Furthermore, five HICs who had relatively poor HIV-suppressive CD8+ T cell capacities were identified (weak responder HICs). Among them, at least three had highly replicative viruses suggesting that there might be another virus control mechanism playing a role in these individuals. My results on HIV controllers support the value of CD8+ T cell suppression assay for measuring the effective anti-viral CD8+ T cell response since it reflects the concurrence of specificity, magnitude, and quality of response. For this, I have developed a rapid, and convenient form of the viral suppression assay based on the intracellular detection of p24 by flowcytometry. This assay was directly

applied to a collaborative study which was to investigate the effect of antigen sensitivity of CD8+ T cells on the magnitude of HIV-suppressive capacity. On the other axis, I investigated the possibility of an animal model for understanding the mechanism of durable virus control in HIV controllers by characterization of a subset of cynomolgus macaques spontaneously controlling SIVmac251 Infection. Unlike HICs, the CD8+ T cell mediated anti-viral capacity doesn’t seem to be different from that observed in viremic or ART animals. In fact, the capacity of CD8+ T cell ex vivo to suppress SIV infection doesn’t seem to be related to either the route of infection or the viral loads. These results suggest that, differently from what is believed to occur in HIC, the antiviral capacity of circulating CD8+ T cells in the SIV controllers is not determinant to their capacity to spontaneously control the virus in vivo. Identification of the mechanisms of virus control in SICs despite weak antiviral capacity of blood CD8 T cells might provide us with some clues for better understanding the control of HIV infection in HICs.In conclusion, ex vivo capacity of CD8+ T cells to suppress HIV-1 infection is peculiar to HIV controllers (HIC) and the suppressive capacity correlated strongly with the frequency of Gag-specific CD8+ T cells; however, some HICs are able to tightly control the virus with relatively poor HIV-1 suppressive CD8+ T cell capacity suggesting other possible mechanisms. I have developed a rapid and convenient from of viral suppression assay which measure the effective anti-viral CD8+ T cell response. Unlike in HIV controllers, antiviral capacity of circulating CD8+ T cells is not determinant in the spontaneous control of viremia observed in the early phase of chronic infection in SIV controllers.