Correlates of cytotoxic T-lymphocyte-mediated virus control: implications for immune suppressive infections and their treatment

A very important question in immunology is to determine which factors decid e whether an immune response can efficiently clear or control a viral infec tion, and under what circumstances we observe persistent viral replication and pathology. This paper summarizes how mathematical models help us gain n ew insights into these questions, and explores the relationship between ant iviral therapy and long-term immunological control in human immunodeficienc y virus (HIV) infection. Mie find that cytotoxic T-lymphocyte (CTL) memory, defined as antigen-independent persistence of CTL precursors, is necessary for the CTL response to dear an infection. The presence of such a memory r esponse is associated with the coexistence of many CTL clones directed agai nst multiple epitopes. If CTL memory is inefficient, then persistent replic ation can be established. This outcome is associated with a narrow CTL resp onse directed against only one or a few viral epitopes. If the virus replic ates persistently, occurrence of pathology depends on the level of virus lo ad at equilibrium, and this can be determined by the overall efficacy of th e CTL response. Mathematical models suggest that controlled replication is reflected by a positive correlation between CTLs and virus load. On the oth er hand, uncontrolled viral replication results in higher loads and the abs ence of a correlation between CTLs and virus load. A negative correlation b etween CTLs and virus load indicates that the virus actively impairs immuni ty as observed with HIV. Mathematical models and Experimental data suggest that HIV persistence and pathology are caused by the absence of sufficient CTL memory. We show how mathematical models can help us devise therapy regi mens that can restore CTL memory in HIV patients and result in long-term im munological control of the virus in the absence of life-long treatment.