A Journal of Virology study shows that HIV infection of monocytes, high levels of LPS, and viral infection of BBB cells are the key to the crossover.
A component of certain intestinal bacteria, called lipopolysaccharide (LPS), helps the virus penetrate the blood-brain barrier (BBB), according to researchers at Albert Einstein College of Medicine of Yeshiva University.
“HIV infection of monocytes increases their capacity to cross even an intact BBB, HIV infection in the gut releases LPS into the bloodstream allowing it to erode the BBB, and HIV infection of the cells of the BBB makes them more sensitive to the deleterious effects of LPS,” explains Harris Goldstein, Ph.D., director of the Einstein-Montefiore Medical Center for AIDS Research and senior author of the study.
In a 2006 study, NIH 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 LPS, a component of certain bacteria that are normally confined to the intestine but leak out due to HIV infection.
In addition, previous animal studies had shown that exposure to elevated LPS levels compromised the integrity of the BBB. “So we hypothesized 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.
Dr. Goldstein and colleagues created a double transgenic mouse line, HIV/GFP-TG. These mice carried all the genes needed to make HIV and the gene that codes for green fluorescent protein (GFP). Next, they isolated millions of HIV/GFP-producing monocytes as well as monocytes from the GFP-TG mice, which produce GFP alone.
They then injected each type of monocyte into control mice. After four days, the researchers examined the brains of the injected mice to see whether monocytes from the bloodstream had crossed their BBB’s.
The investigators found 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.
To figure out whether LPS’ role, the 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 BBB’s. After three hours, half the mice were intravenously injected with HIV/GFP monocytes, while the remaining mice were intravenously injected with GFP-producing monocytes that were otherwise normal.
After four days, monocytes were readily detected in the brains of about 25% of mice pretreated with LPS and then injected with HIV/GFP producing monocytes. By contrast, monocytes could not be detected in the brains of any of the 15 GFP-TG mice. “Clearly, HIV-infected monocytes uniquely benefit from the LPS that is present in high amounts in the blood of HIV-infected people,” Dr. Goldstein states.
The scientists finally tested the effects of systemic HIV infection. They used the HIV-TG mouse strain, in which HIV is known to replicate inside brain cells associated with the BBB. These HIV-TG mice along with control mice were injected with LPS and three hours later, intravenously injected with HIV/GFP monocytes.
After four days, HIV-producing monocytes could be detected in the brains of about 25% of the control mice. By contrast, more than twice as many, or 70%, of the brains of HIV-TG mice that support systemic HIV infection contained HIV-producing monocytes. Additionally, the HIV-producing monocytes were three times more numerous in the brains of HIV-TG mice than in the brains of control mice.
Drs. Hongwei Wang and Jinglin Sun also from the, collaborated on the project, which were published in the August issue of the Journal of Virology