Acute HCV infection commonly progresses to chronicity in 65-85% of cases [54
]. Comparable rates of chronicity have been observed for certain indigenous peoples, but populations of an enhanced resistance to chronicity also exist. In northern AN populations chronicity rates are analogous to non-indigenous peoples [40
]. In contrast, HCV RNA was generally not observed in HCV antibody positive individuals in one northern Canadian Inuit community [25
]. Likewise, HCV chronicity was below 6% for Greenland Inuit peoples [26
In the Nebraskan clinical study, 75% of the HCV seropositive individuals were also HCV RNA positive, indicating that three quarters of acutely infected individuals developed a chronic infection [29
]. Conversely, significantly reduced rates of progression to chronic HCV infection have been detected for indigenous peoples in the west coast and plains regions of Canada. In IDU cohorts of BC, self-identified Aboriginals that were HCV antibody positive demonstrated HCV RNA negativity at an odds ratio of 2.9 (95% CI 2.0 to 4.3; p<0.001) relative to non-Aboriginals; strongly suggestive of enhanced spontaneous clearance [55
]. A Manitoban FN community survey found that of the 2.2% anti-HCV positive individuals, none tested positive for HCV-RNA [28
]. The corresponding provincial testing center further observed a reduced HCV chronicity in FN relative to non-FN patients, despite HCV infection being suspected as the cause of liver dysfunction in these patients [56
]. For other US AI and Canadian Aboriginal peoples the rate of progression to chronic HCV infection has not been investigated.
Analyses of re-infection rates in IDU cohorts have been inconclusive as to whether spontaneous clearance of HCV infection is protective against subsequent re-infection [57
]. It remains to be determined if re-infection rates differ between AI/AN and Aboriginal population relative to non-indigenous counterparts.
A variety of elements could contribute to improved rates of self-limited infection in certain Aboriginal populations including individual age at time of exposure and viral factors. Upon pediatric exposure spontaneous clearance of HCV infection can occur in 30% -50% of cases, although for vertical transmission rates appear considerably lower (9%) [62
]. A younger age of exposure is a not likely a critical factor in the enhanced clearance observed within older Aboriginal cohorts, as the acquisition of HCV infection is associated moving into an urban center [44
]. However, with young women increasingly affected by HCV infection, pediatric diagnoses may rise for indigenous populations. Due to the strong association of HCV infection with IDU limited differences in dose and route would account for racial differences in enhanced clearance of acute HCV infection. Yet again, it is unknown if emerging transmission routes will alter the potential for self-limited HCV infection, especially in HIV co-infection individuals (see below).
Another possibility is that physiological characteristics unique to AI/AN and Aboriginal peoples may support an enhanced capacity to spontaneously clear HCV infection. HCV chronicity has been associated with host genetics and viral impairment of host immunity. Thus, we have been investigating whether differences in immunity between Aboriginal and non-Aboriginal populations to allow for more effective clearance of acute HCV infection.
Interleukin (IL)-10 is an anti-inflammatory cytokine that can inhibit the T cell interferon (IFN)-γ production that is associated with spontaneous HCV clearance [65
]. The ability of HCV core protein upon initial viral exposure to trigger immune cells such as monocytes (a population of cells in peripheral blood mononuclear cells, PBMC) to produce IL-10 is considered critical in this process [66
]. In addition, individuals with a reduced genetic tendency to produce IL-10 appear less likely to progress to chronic infection [67
]. Genetic studies by our lab and others indicate that Manitoban FN and Métis populations have a reduced genetic tendency to produce IL-10 compared to non-Aboriginals [70
]. Moreover, we found that PBMC from virally-naïve FN individuals produced significantly less IL-10 in response to HCV core protein than cells isolated from non-FN individuals, suggesting that FN cells were not as susceptible to immune deregulation upon first encounter with the virus [70
We further evaluated whether differences in killer Ig like receptors (KIR) gene polymorphisms might influence spontaneous clearance in Aboriginals. KIRs are involved in CD8 T cell and natural killer cell cytotoxic immunity against viruses. Unique KIR gene profiles consisting of a greater presence of activatory genes have been published for patients with self-limited or benign HCV infection outcomes relative to patients with deteriorated disease courses [73
]. The disparities in KIR gene profiles of virally naïve Aboriginals as compared to non-Aboriginals paralleled these disparities reported for better as compared to worse outcomes for HCV infection, suggesting the further involvement of biological processes in racial trends of HCV chronicity [72
]. Coincidently, the unique KIR gene profile and genotypes of Manitoban Aboriginals were similar to other KIR analyses performed within indigenous peoples throughout the Americas; whereas, data from Manitoban Caucasians reflected that of Caucasian globally [72
]. This might be accounted for by a common ancestry or an abrupt immune selection such as the “old world” disease epidemics that swept through indigenous communities [75
]. A more aggressive immunity could have selected for survival under such harsh conditions, resulting in these genetic profiles being passed to the next generations. We are continuing to examine cytokine and KIR profiles in Aboriginal and Caucasian patients with self-limited or chronic HCV infection in an attempt to determine biological factors contributing to HCV chronicity in Manitoban Aboriginals. Taken together, within certain Aboriginal populations specific pro-inflammatory or activatory immune characteristics may be linked to more effective clearance of acute HCV infection. The contribution of other variables should also be considered in understanding this phenomenon.