MicrobiologyBytes

HIV mutation and the immune response

As a result of its high mutation rate, human immunodeficiency virus (HIV) can evade recognition by the host immune response through the generation of virus variants, 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 has been difficult to investigate the dynamics of immune escape.

Researchers from Utrecht University in The Netherlands have developed a new mathematical model that illustrates how HIV evades the immune system. The computational model of HIV infection consists of several CTL clones that can recognize specific parts of virus proteins called “epitopes”. The simulation makes it possible follow the dynamics of immune escape in detail and helps to interpret longitudinal data of real HIV infections by modeling detailed interactions between a mutating virus and the immune system. HIV avoids recognition by the human immune response through the generation of virus variants called “escape mutants”. This prevents effective control of virus replication, eventually causing HIV-infected patients to progress to AIDS. However, it remains difficult to fully understand the dynamics of immune escape, as data from infected patients is relatively sparse. The new work uses computer simulations to help interpret longitudinal data derived from HIV-infected patients. These illustrate that the virus usually evades the immune response very slowly, on a timescale lasting years. Depending on the diversity of the host immune system, the virus will either be controlled effectively or accumulate detrimental mutations.

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Interestingly, changing the relative sizes of the CTL clones leads to a different evolution path for 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 by imposing a fitness cost in virus replication or infectivity. That might have important implications for disease progression.

Dynamics of Immune Escape during HIV/SIV Infection. 2008 PLoS Comput Biol 4(7): e1000103
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.

This entry was posted on Monday, July 21st, 2008 at 9:00 am and is filed under Biology, Health, HIV/AIDS, Medicine, Microbiology, Podcast, Science, Virology. You can follow any responses to this entry through the RSS 2.0 feed. Both comments and pings are currently closed.