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Leaky Gut Linked to HIV in Brain, Dementia NEW YORK -- August 20, 2008 -- An article in the August issue of the Journal of Virology reports that the HIV virus manages to leak out of the gut, enter the bloodstream, and cross into the brain in up to 20% of people with HIV, resulting in HIV-associated dementia and other cognitive disorders. Scientists at the Albert Einstein College of Medicine of Yeshiva University, New York, New York, have found strong evidence that a component of the cell walls of intestinal bacteria -- a chemical present in high levels in the blood of HIV-infected people -- helps HIV to penetrate the usually impregnable blood brain barrier (BBB). This finding could lead to strategies for preventing HIV from entering the brain and causing serious complications. "Previous research has suggested that it is not individual HIV viruses that get into the brain but rather HIV-infected immune cells known as monocytes," says senior author Dr. Harris Goldstein, Einstein-Montefiore Medical Center for AIDS Research, New York, New York. "Using an animal model, we wanted to find out first of all whether being infected with HIV enables monocytes to do what they don't usually do -- escape from blood vessels and enter brain tissue." Overcoming HIV's inability to infect mice, Dr. Goldstein and his colleagues had previously created a transgenic mouse line, HIV-TG mice, equipped with all the genes needed to make HIV. The HIV-TG mice produce HIV in those cells, including monocytes and T cells, in which the virus multiplies in people. The HIV-TG mice were then bred with another transgenic mouse line, GFP-TG mice, containing the gene that codes for green fluorescent protein (GFP). The result: a double transgenic mouse line, HIV/GFP-TG mice, whose HIV-infected monocytes carried the GFP gene. Thus the monocytes could be detected -- either by looking for glowing green cells under the microscope or by using polymerase chain reaction, which is capable of detecting the DNA of the GFP gene. Next, the researchers isolated millions of monocytes -- HIV/GFP-producing monocytes from the HIV/GFP-TG mice, and monocytes from the GFP-TG mice producing GFP alone. They then injected each type of monocyte into the control mice. Four days later, there was no sign of monocytes in the brains of any of the mice injected with uninfected GFP monocytes. However, ultrasensitive DNA analysis showed that HIV/GFP monocytes were present at very low levels in the brains of nearly one-third of the mice injected with the HIV-producing monocytes. "These results demonstrated very clearly that being infected with HIV somehow gives monocytes the capacity to cross an intact BBB," says Dr. Goldstein. "But we also suspected that something else was making it easier for HIV-infected monocytes to breach the defenses protecting the brain from infection." In 2006, researchers reported that HIV infection breaks down barriers in the intestine that normally prevent intestinal bacteria from entering the bloodstream. The blood of HIV-infected people was found to contain markedly elevated levels of lipopolysaccharide (LPS), a component of certain bacteria that are normally confined to the intestine but leak out due to HIV infection. In addition, animal studies had shown that exposure to elevated LPS levels compromised the integrity of the BBB. "So we hypothesised that the combination of HIV-infected monocytes and elevated LPS levels would amplify the ability of HIV to cross the BBB and get into the brain," says Dr. Goldstein. To test this hypothesis, his team injected control mice with very low doses of LPS that were comparable to the levels in the bloodstream of HIV-infected individuals and would only minimally weaken their BBBs. Three hours later, half the mice were intravenously injected with HIV- and GFP-producing monocytes, while the remaining mice were intravenously injected with GFP-producing monocytes that were otherwise normal. Four days later, monocytes could not be detected in the brains of any of the 15 mice that were pretreated with LPS and then injected with normal monocytes producing GFP alone. By contrast, monocytes were readily detected in the brains of about 25% of mice pretreated with LPS and then injected with HIV- and GFP-producing monocytes. "Clearly, HIV-infected monocytes uniquely benefit from the LPS that is present in high amounts in the blood of HIV-infected people," says Dr. Goldstein. "So when HIV-infected monocytes are 'knocking on the door' of the BBB and starting to crack it open, the LPS facilitates their entry by making the BBB more permeable, apparently by weakening blood vessel structure." Having a systemic HIV infection also helps soften up the BBB. Further results demonstrated that "HIV infection of cells associated with the BBB, in conjunction with LPS exposure, contributes to BBB breakdown," says Dr. Goldstein. These findings could lead to preventive or therapeutic strategies. To help maintain the integrity of the BBB in HIV-infected people, says Dr. Goldstein, one approach might be to monitor the LPS level in their bloodstream and then reduce elevated levels. "We may be able to use antibiotics that kill intestinal bacteria that make LPS, and drugs are already available that can bind to LPS and clear it from the bloodstream," says Dr. Goldstein. "Ideally, we would promptly start newly diagnosed HIV-infected patients on a treatment to reinforce their BBBs so that HIV can't penetrate it. Perhaps we could even strengthen the BBBs of people who've been infected for quite a while. But before we can prevent the tragedy of HIV-associated dementia, we need to better understand the mechanism by which these molecular and cellular 'punches' interact to undermine the BBB." SOURCE: Albert Einstein College of Medicine E-mail this page to a friend or colleague! To print, use this version