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Inefficient immune killer cells abet HIV infection

HIV attacks the immune system by infecting and killing helper T lymphocytes (also called CD4 T cells), the white blood cells responsible for mobilizing the mediators of an immune response. It's thought that the response of another type of T cell--the cytotoxic T lymphocyte (CTL)--may be responsible for a large proportion of these deaths because CTLs recognize and kill infected cells. Based on this assumption, current HIV vaccine strategies are focusing on the CTL response. But it has proven difficult to study how much ultimate control the CTL response exerts over the virus in humans.

In a new study published on-line in the open-access journal PLoS Biology , Becca Asquith, Angela McLean, and their colleagues turned to mathematical modeling to measure the overall effect of the CTL response on the lifespan of infected cells in patients with HIV. Applying different metrics to 28 independent datasets spanning 14 years, the researchers found that CTLs kill roughly 10 million infected cells a day--but, surprisingly, this represents just a fraction of infected cell deaths.

When a virus infects a cell, viral proteins get chopped up into short fragments called epitopes that bind to human leukocyte antigen (HLA) class I molecules and are presented on the infected cell surface. Viral epitopes bound to the HLA molecules act as a signal to the CTL immune response, informing it that the cell is infected and needs to be killed. HIV can develop mutations in its epitopes that allow the virus to escape detection by CTL, often by abrogating HLA binding. The observation that these escape variants outgrow the wild type is much cited evidence that the CTL response exerts selective pressure on the virus.

Asquith et al. have taken this argument one step further and quantified the rate at which escape variants grow out in order to estimate the CTL selective pressure. They developed a model of infected cell dynamics to quantify the rate of escape and fitness cost
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Contact: Paul Ocampo
press@plos.org
415-624-1224
Public Library of Science
13-Mar-2006


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