Early CTL targeting differs in B57 slow vs. fast progressors

Catherine Brennan 
University of California, Los Angeles
Basic Biomedical Sciences

Although our immune systems are able to help us recover from almost every kind of viral infection, HIV is an exception, and if not treated, leads to AIDS disease within 8 years of infection in most people.  Intriguingly, a small percentage of people are able to exert effective immune control of the virus and delay illness for much longer, beyond 25 years in some cases.  Since the goal of an HIV vaccine is to elicit effective immune responses to the HIV virus, these rare individuals offer an excellent opportunity to identify the features of a successful immune response to HIV. 

One obstacle to this type of investigation is that the immune responses in the first months after infection are the most critical to long-term disease resistance outcomes.  However, the long lag between infection and evidence of long-term immune control has hampered efforts to link early immune events with successful long-term outcomes.  The Multicenter AIDS Cohort Study (MACS) has volunteers from at-risk and HIV-infected American populations who have contributed samples every six months for over 25 years, which have been cryopreserved in a longitudinal archive. 

In a preliminary correlation study, we have been able to take advantage of these unique samples and go back and compare the early immune responses in those people who have been able to control HIV without medication with the immune responses in those who have not.  We were intrigued to find a particular immune response that was common in those who eventually controlled HIV, but rare in those who did not.  This correlation suggests that this particular immune response, in which cytotoxic (killer) T cells target of a part of the HIV capsid protein, may directly confer protection.  In order to test this hypothesis, we will conduct a pilot study in which we will culture the cytotoxic T cells from the volunteers who have demonstrated long-term immune control, and compare the ability of the cells that target different parts of the HIV capsid protein to (a) control HIV replication in a petri dish and (b) recognize the virus even when its capsid protein mutates.  If we find that the cytotoxic T cells we identified in the correlation study have superior antiviral activity in culture, then future studies will investigate both the cellular characteristics that underlie this antiviral effectiveness, and the early events in HIV infection that lead to the production of this type of cytotoxic T cell.  By understanding the cellular and molecular mechanisms of natural immune control of HIV, we can try to mimic these mechanisms when designing a vaccine.