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HIV, the virus that causes AIDS, is the cause of one of the most far-reaching and destructive epidemics in modern times. Responsible for approximately 1.8 million deaths and more than 2.5 million new infections annually, HIV is a major public health concern, particularly in the developing world. HIV-1, the most common and virulent strain of the virus, has been studied extensively by researchers hoping to better understand the virus’s life cycle and develop treatments that disrupt its ability to infect and reproduce. One of the greatest barriers to effective treatment and clearance of HIV-1 is the virus’s astonishing capacity for immune evasion. From constant mutation to active subversion of the body's immune system, HIV is a particularly difficult pathogen to eliminate. In a paper published in PLoS: Pathogens in March of 2010, researchers from the Institut Pasteur examined one method by which HIV-1 is able to evade the natural killer (NK) cells of the innate immune system and establish a persistent infection, providing both a better understanding of HIV-1 immune evasion and a possible target for future HIV treatments.
Under normal conditions, viruses and virus particles are taken up by a subset of the host’s white blood cells known as dendritic cells (DCs). The DCs act as the immune system’s sentries, scouting the body’s tissues for foreign particles or pathogens and presenting them to other immune cells to stimulate a response. DC function is closely regulated by the interactions that take place with NK cells following infection. When inflammation occurs at the site of an infection or injuries, chemical signals known as chemokines cause NK cells to migrate to the infection site. Upon arrival, NK cells interact with DCs, sending signals that may cause the DCs to mature, and receive activating signals from the DCs. If an NK cell encounters a DC that has been infected by a virus or other intracellular pathogen, the NK cell will kill the infected cell by inducing a process known as apoptosis. When the infected DCs undergo apoptosis – also known as programmed cell death – the virus inside them can no longer replicate. This process is essential to the immune system’s ability to clear a virus from the body, particularly during the early stages of infection. However, previous research has suggested that HIV positive people are deficient in killing DCs that are infected with HIV-1, causing the infected DCs to act as a reservoir in which the virus can replicate without interference. In this paper, the researcher set out to determine the methods by which HIV-1 is able to prevent NK cells from killing infected DCs.
During the course of their experiment, the researchers had three main goals: (1) to determine what pathway is used by NK cells to kill infected DCs, (2) to determine what was stopping the NK cells from killing the infected DCs, and (3) to identify the signal or signals responsible for the defect in infected DC killing.
The primary method by which NK cells kill their targets is known as the “perforin/granzyme” pathway. In this method, the NK cells release particles known as granules. These granules contain perforin, which pokes holes in the target cell’s membrane, and granzyme, which enters the target cell through these holes and breaks down the cell’s proteins and DNA, killing it. While this is the most common cell-killing pathway used by NK cells, the researchers found that NK cells grown with DCs contained no more granules than those grown without DCs. This suggested that NK cells were not using the perforin/granzyme pathway to kill infected DCs. The researchers were able to determine that NK cells grown with DCs expressed elevated levels of another apoptosis-related protein, TNF-related apoptosis-inducing ligand (TRAIL), on their cell surface. This protein binds to DR4, a receptor on the surface of the DCs, and induces apoptosis.
Having determined how NK cells are able to kill infected DCs, the researchers moved on to figuring out how HIV-1 prevents DC death by apoptosis. The researchers examined HIV-infected DCs (DCHIV) and determined that the decreased susceptibility to NK cell killing was not due to defects in the expression of TRAIL or DR4, but was a result of the increased expression of two proteins on the membrane of DCHIV cells. In DCHIV cells infected with an actively replicating virus, the expression of these two proteins, c-IAP2 and c-FLIP, was increased dramatically. Together, these two proteins act as anti-apoptotic signals, preventing the NK cells from killing infected DCs, an effect that was counteracted when the researchers blocked the function of c-IAP2 and c-FLIP.
Finally, the researchers at the Institut Pasteur were able to identify a signaling protein that was at least partly responsible for the DCHIV resistance to NK cell killing. The authors, who had previously examined the role of NK/DC interactions in the maturation of virus-infected DCs, identified HMGB-1 as an important signaling molecule for this process. After observing increased expression of HMGB-1 in their DCHIV/NK cell cultures, the authors suspected that this signaling protein might have something to do with preventing the DCHIV from being killed. As it turns out, they were right. Shutting down the function of HMGB-1 prevented the DCHIV cells from expressing c-IAP2 and c-FLIP, allowing the NK cells to kill them through the TRAIL/DR4 pathway.
This research holds some interesting implications for the future of HIV research and treatment. A large part of what makes HIV so difficult to get rid of is its ability to sustain infection inside the host’s immune cells, successfully dodging attempts to eradicate it. If the research in this article can be applied in vivo, it could represent a significant step forward in helping the body to rid itself of HIV infection. Drugs that disable either the expression of HMGB-1 or the anti-apoptotic function of c-IAP2 and c-FLIP would enable NK cells to destroy infected DCs, eliminating a crucial reservoir of HIV infection. HMGB-1 and its various anti-apoptotic and infection-stimulating functions have become the focus of a significant body of research, and as immunologists begin to understand the structure and function of HMGB-1 more fully, they will hopefully be able to apply these findings to new, effective treatments.
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