Although many individuals infected with the hepatitis C virus (HCV) are naturally able to control levels of the virus with their immune systems, those who also become infected with HIV, the virus that causes AIDS, may lose that ability. In a report in the December issue of PLOS Medicine, a group of researchers from the Partners AIDS Research Center at Massachusetts General Hospital (PARC-MGH) report one of the first studies of how HIV infection impacts immune system functions involved with HCV control. Their findings suggest that beginning antiretroviral therapy earlier than is generally recommended may help preserve HCV control in patients infected with both viruses.
"The global burden on health of chronic viral infections is immense, and HCV and HIV are chief among culprit viruses," says Arthur Kim, MD, of PARC-MGH, co-first author of the PLOS Medicine report. "Due to shared routes of transmission, infection with both viruses is common. Unfortunately, HCV behaves as an opportunistic infection in the presence of HIV and is becoming a leading cause of illness and death in persons with HIV."
In order to examine immune system factors associated with spontaneous control of HCV and how that control is altered by HIV infection, the researchers enrolled four groups of participants: 60 were infected with both viruses, and half of those had low HCV levels upon entering the study. The other two groups of 17 participants were infected with HCV only, with one group successfully controlling viral levels. Spontaneous HCV control is known to rely on the activity of CD4 helper T cells specifically targeted against the virus, and destruction of CD4 cells by HIV underlies the immune deficiency that characterizes AIDS. Therefore the researchers measured participants' T cell response to HCV at the outset of the study and at two- to six-month intervals during the study period.
The results showed that those individuals able to maintain low HCV levels in spite of HIV coinfection had stronger virus-specific responses for both CD4 T cells and the CD8 "killer" T cells than did those with elevated HCV counts. Not surprisingly, participants infected only with HCV had even more powerful antiviral T cell responses. About a quarter of those infected with both viruses who originally controlled HCV levels lost control during the two-and-a half-year study period, and their increased virus levels corresponded with an overall drop in CD4 T cells. None of the viral controllers who were infected with HCV alone had any increase in viral levels during the study period. Loss of protective responses and susceptibility to recurrent HCV infection may help to explain the higher rates of persistent HCV observed in subjects who are HIV/HCV coinfected, compared to those with HCV alone.
In analyzing factors that might be associated with the loss of HCV control in those infected with both viruses, the researchers made a surprising discovery. The factor most powerfully associated with maintaining HCV control was not the CD4 T cell count upon entering the study but the lowest previously recorded or ‘nadir' CD4 count. That finding suggests that, for individuals infected with both viruses, beginning antiretroviral treatment before CD4 levels drop too low to maintain HCV responses may be desirable.
The researchers also found that, among those whose HCV levels rose, individuals who maintained some T cell responses had lower viral levels than did those with little or no T cell response. This suggests that the immune system retains a level of secondary immunity against HCV – the kind of ‘memory' response against a previously encountered pathogen seen in many infections.
"Currently a nationwide trial is recruiting people for a study examining whether earlier treatment of HIV will improve hepatitis C treatment outcomes," Kim says. "Part of this study will investigate how earlier treatment may affect immune responses. It also will be important to follow the impact of loss of HCV control on liver disease, since this will probably have important consequences for patients with HIV." Kim is an instructor in Medicine at Harvard Medical School.
Bruce Walker, MD, director of the Partners AIDS Research Center at MGH and a Howard Hughes Medical Institute (HHMI) investigator is senior author of the PLOS Medicine report, and Julian Schulze zur Wiesch, MD, of PARC-MGH and HHMI is co-first author. The study's co-authors are Thomas Kuntzen, MD, Joerg Timm, Daniel Kaufmann, MD, Jared Duncan, Andrea Jones, Benjamin Davis, MD, Rajesh Gandhi, MD, Gregory Robbins, MD, Todd Allen, PhD, and Georg Lauer, MD, of PARC-MGH, Raymond Chung, MD, MGH Gastroenterology; and Alysse Wurcel, Lemuel Shattuck Hospital, Boston. The study was supported by grants from the National Institutes of Health, the Campbell Foundation, the American Liver Foundation, the German Academic Exchange Service, Doris Duke Charitable Foundation and the Howard Hughes Medical Institute.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare System, a Boston-based integrated health care delivery system.
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