Dynamics of Immune Escape during HIV/SIV Infection

Open Access
Publisher Website
Google Scholar
Abstract
Several studies have shown that cytotoxic T lymphocytes (CTLs) play an important role in controlling HIV/SIV infection. Notably, the observation of escape mutants suggests a selective pressure induced by the CTL response. However, it remains difficult to assess the definite role of the cellular immune response. We devise a computational model of HIV/SIV infection having a broad cellular immune response targeting different viral epitopes. The CTL clones are stimulated by viral antigen and interact with the virus population through cytotoxic killing of infected cells. Consequently, the virus population reacts through the acquisition of CTL escape mutations. Our model provides realistic virus dynamics and describes several experimental observations. We postulate that inter-clonal competition and immunodominance may be critical factors determining the sequential emergence of escapes. We show that even though the total killing induced by the CTL response can be high, escape rates against a single CTL clone are often slow and difficult to estimate from infrequent sequence measurements. Finally, our simulations show that a higher degree of immunodominance leads to more frequent escape with a reduced control of viral replication but a substantially impaired replicative capacity of the virus. This result suggests two strategies for vaccine design: Vaccines inducing a broad CTL response should decrease the viral load, whereas vaccines stimulating a narrow but dominant CTL response are likely to induce escape but may dramatically reduce the replicative capacity of the virus. As a result of their high mutation rate, HIV and its counterpart SIV in non-human primates can evade recognition by the host immune response through the generation of viral variants, the so-called escape mutants. This avoidance of cytotoxic T lymphocyte (CTL) mediated killing seems to be one of the major reasons why virus replication is not controlled effectively. However, it remains difficult to investigate the critical properties of the dynamics of immune escape. To this end, we developed a new computational model of HIV/SIV infection consisting of several CTL clones that can recognize specific parts of viral proteins, i.e., epitopes. The simulations allow us to follow the dynamics of immune escape in detail and help to interpret longitudinal data of HIV/SIV infections. Interestingly, changing the relative sizes of the CTL clones leads to a different evolution of the virus. Instead of reducing the number of infected cells, an alternative strategy of vaccine design could be to reduce the replicative capacity of the virus that might have implications for disease progression.