BOSTON -- Damage to the gastrointestinal tract is common in patients with AIDS, and it's not just a minor complication of the disease. Researchers suspect that this damage actually contributes to activation of the patient's immune system, the development of immune deficiency, and ultimately the progression of AIDS.
Scientists have little information about how this damage to the gut occurs, but now a team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and Washington University School of Medicine has uncovered new clues. The findings, published online today in the journal
Cell, implicate the presence of potentially pathogenic viruses other than those that cause AIDS and suggest that a better understanding of how these non-HIV viruses contribute to disease progression might provide an opportunity to explain and eventually intervene in the processes that lead to advanced AIDS.
To investigate what causes AIDS-related gastrointestinal damage, Dan Barouch, MD, PhD and colleagues studied monkeys infected with SIV, the monkey counterpart to HIV. "Interestingly, natural hosts for SIV such as African green monkeys can carry large amounts of the virus without developing AIDS," says Barouch, the Director of the Center for Virology and Vaccine Research at BIDMC and Professor of Medicine at Harvard Medical School Other monkeys such as rhesus monkeys become very sick when infected with SIV.
The team looked to a sequencing method called next-generation sequencing to examine all of the bacteria, viruses, and other organisms residing in the gastrointestinal tract of three groups: rhesus monkeys with pathogenic SIV infection, African green monkeys with nonpathogenic SIV infections, and a control group of monkeys without SIV infections.
Using the sequencing method on samples of feces from the monkeys, "we found that the gastrointestinal tract of the animals with AIDS contained a large number of previously undescribed viruses-including potential pathogens. But we did not see any obvious changes in the bacteria," says Barouch. Specifically, he explains, SIV infection was associated with a greater than10-fold increase in the number of sequences from viruses at 24 weeks postinfection But, he adds, this expansion of the intestinal virome was associated only with pathogenic SIV infection in the rhesus monkeys, not with nonpathogenic SIV infection of the African green monkeys.
Using very conservative criteria, the researchers went on to identify at least 32 previously undescribed viruses from multiple pathogenic groups found in the gastrointestinal tracts of monkeys infected with pathogenic SIV. (There may be many more, says Barouch, explaining that because criteria were conservative, both the size and the pathogenic potential of the intestinal virome in SIV-infected animals may have been significantly underestimated, and viruses that infect the intestine but are shed at very low levels may have been missed.)
Of particular interest, they add, is that the presence of adenoviruses during pathogenic SIV infection caused inflammation of the intestines, indicating that infection with these viruses may be linked to intestinal damage during AIDS progression. Barouch notes that some of the viruses-such as parvoviruses-detected in the feces of monkeys with AIDS were also found circulating in the animals' blood.
In addition, the scientists add, many of these were RNA viruses, meaning that their genetic material is made up of RNA rather than DNA. "This is the first time anyone has looked at both DNA- and RNA-based organisms in the fecal matter in association with AIDS. The striking finding of so many RNA viruses to go along with DNA viruses opens up the broader issues of whether the field of metagenomics-the study of microbial communities-now needs to shift to doing total nucleic acid analysis rather than focusing on bacteria and DNA as has often been the case," says senior author Herbert Virgin, MD, PhD, of the Washington University School of Medicine, in Saint Louis.
The scientists speculate that intestinal viruses may enable SIV infection to progress to AIDS by fostering intestinal damage that allows the release of bacterial, viral, fungal, and other activators of the immune system into host tissues and blood.
"We now want to follow animals to evaluate the timing of the expansion of the intestinal virome in relation to clinical disease progression and to assess interventional strategies to block this process," says Barouch.
In addition to providing new information on how AIDS advances -- and therefore how to potentially intervene to slow it down -- the results suggest that the viruses found in AIDS patients' intestines could indicate how progressive their disease will be. "Whether this may have diagnostic or prognostic value remains to be determined based on ongoing and future studies," says Barouch.
Study coauthors include Scott A. Handley, Larissa B. Thackray, Guoyan Zhao, Rachel Presti, Andrew D. Miller, Lindsay Droit, Peter Abbink, Lori F. Maxfield, Amal Kambal, Erning Duan, Kelly Stanley, Joshua Kramer, Sheila C. Macri, Sallie R. Permar, Joern E. Schmitz, Keith Mansfield, Jason M. Brenchley, Ronald S. Veazey, Thaddeus S. Stappenbeck, and David Wang.