Grant: CIHR Fellowship

While antiretrovirals (ARV) effectively control viral replication in HIV+ patients, there is no cure for HIV infection. HIV infects CD4 T cells, the "targets" for CD8 T lymphocytes (CTLs), which attempt to kill them. While CTLs fail to completely clear the infection, they are vital for controlling the virus. Some HIV+ patients control HIV better than others, due to strong CTL responses. These "controllers" live with HIV, without ARV, for decades without progressing to AIDS, appearing "functionally" cured. In contrast, patients who progress to AIDS (progressors) have overworked CTLs, which become "exhausted", losing the ability to kill infected targets. This exhaustion is characterized by appearance of negative proteins, CTLA-4 and PD-1, on the CTL surface, making them less effective. Further, control of HIV is mediated by CTL ability to recognize "vulnerable" areas of HIV proteins. While CTL from controllers respond to vulnerable proteins better than CTL from progressors, it's unclear if lack of a response in progressors is due to the ability to recognize the vulnerable proteins or to exhaustion. The goal of this study is to understand what makes an effective CTL response capable of controlling HIV infection. Our hypothesis is that CTLs from progressors are able to recognize vulnerable proteins, but require manipulation of CTLA-4/PD-1 to enhance the response. To reach this goal, immunological techniques will be used to compare the quality of CTL responses to vulnerable proteins in progressors and controllers. Specifically, we will assess CTLA-4/PD-1, and study how these exhaustion markers affect the development of CTL responses to vulnerable proteins. Characterizing these responses will aid with therapeutic vaccine design for early ARV-treated patients. Directing CTL responses to vulnerable proteins and boosting these responses by disrupting CTLA-4/PD-1 (therapies used in cancer clinics), could allow the immune system to achieve a "functionally" or fully cured state