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Scientists Decipher HIV ‘Attack Plan’

Findings could influence vaccine design (Mar. 29)

Researchers at Los Alamos National Laboratory and at the University of Pennsylvania have identified previously unknown properties of transmitted human immunodeficiency virus-1 (HIV-1). The viruses that successfully pass from a chronically infected person to another individual not only are resistant to the innate human immune-response mechanism, but are blanketed in a greater amount of envelope protein, which helps them access and enter host cells.

The new findings — published online in the Proceedings of the National Academy of Sciences — may help inform vaccine design and the interpretation of vaccine trials, and may provide new insights into the basic biology of viral/host dynamics of infection, the authors say.

During the course of infection, HIV-1 evolves within the infected person to escape the host’s natural immune response and to adapt to the local environment within the infected individual. Because HIV-1 evolves so rapidly and so extensively, each person acquires and harbors a complex set of viruses that develops over the years of his or her infection. However, when HIV is transmitted to a new person from a partner, typically only a single virus from the diverse set in the partner is transmitted to establish the new infection.

The researchers discovered the specific features that distinguish viruses that successfully move to the new host, compared with the myriad viral forms present in a chronically infected individual.

“The viruses that make it through transmission barriers to infect a new person are particularly infectious and resilient,” said Dr. Bette Korber. “Through this study we now better understand the biology that defines that resilience.”

The team set out to determine whether HIV-1 that is successfully transmitted to a new patient might share distinct biologic properties compared with those of viruses typically isolated from people with long-term, chronic infection. To do this, the investigators cloned a set of intact viruses from acute infection and a set of viruses from chronically infected people, and characterized them by measuring quantities that might be related to the virus’ ability to successfully establish a new infection.

The researchers discovered several clear correlations. For example, transmitted HIV-1 was more infectious and contained more protective ‘envelope’ per virus. Envelope is the protein that the viruses use to enter host cells.

The team identified an additional property that could be a general characteristic of new viral infections: the transmitted HIV-1 was capable of replicating and growing in the presence of interferon-alpha (IFN-alpha). The production of IFN-alpha is part of the innate immune response to a new infection. As soon as a new viral infection is initiated in the body, local immune cells at the site of infection start secreting cytokine molecules, which have general antiviral activity and which can inhibit the production of the newly infected virus. IFN-alpha is one of these potent cytokines.

In the early days of an HIV-1 infection, the body’s innate immune response increases to an intense level, called a “cytokine storm,” which gradually recedes during infection. For newly transmitted HIV-1 to successfully establish infection, it must grow and expand in the new host while facing this "storm." Although typical chronic viruses are sensitive to and inhibited by IFN-alpha, transmitted HIV-1 viruses grew well in its presence.

Source: Los Alamos National Laboratory; March 29, 2013.

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