The persistence of CTL memory.

ABSTRACT

A very important question in immunology is to determine which factors decide whether an immune response can efficiently clear or control a viral infection, and under what circumstances we observe persistent viral replication and pathology. This paper summarises how mathematical models help us gain new insights into these questions, and explores the relationship between anti-viral therapy and long-term immunological control in HIV infection. Particular focus is given to the phenomenon of CTL memory, which I define as long-term antigen-independent persistence of CTLp. Contrary to traditional thinking, theory suggests that antigen-independent persistence of memory CTL is required to clear the primary infection, because this ensures stable and sustained immunological pressure while virus load declines. In the presence of a sustained memory response theory suggests that the CTL population is broad, directed against multiple epitopes. On the other hand, if memory CTL are not sustained in the absence of or at low levels of antigen, then the virus can establish a persistent infection. In this case, the model suggests that the CTL response is narrow, characterised by only one or a few immunodominant CTL clones. Mathematical models and experimental data suggest that HIV persistence and pathology is caused by the absence of a sustained CTL memory response, caused by the impairment of CD4 T-cell help. We show how mathematical models can help us devise therapy regimes that can restore CTL memory in HIV-infected patients and result in long-term immunological control of the virus in the absence of lifelong treatment.