Bacterial translocation

Immune activation is by now well established as the main driver of the progression of HIV infection and its consequences [1–6]. Although HIV-specific killing of CD4 cells plays a major role in the pathogenesis of the acute phase of the infection, it is the continuous and persistent immune activation that characterizes the chronic phase of the infection and that is responsible for the profound CD4 cell attrition eventually resulting in AIDS. Likewise, the presence or absence of immune activation during simian immunodeficiency virus (SIV) infection is responsible for the presence of the AIDS-like disease in rhesus macaques or, for its absence, in the naturally occurring SIV infection in green monkeys and sooty mangabies, respectively [7,8]. HIV infection should, therefore, be perceived as a disease of chronic immune activation that is elicited by the specific immune response to HIV [6,9]. The dramatic clinical success of antiretroviral treatments (ARTs) that effectively suppress viral replication is primarily the outcome of the significant decrease in immune activation and the resultant immune reconstitution. Not surprisingly, therefore, disease progression is better correlated to immune activation, than to CD4 cell or viral load levels [10,11]. However, despite the very effective viral suppression achieved by ART, persistent immune activation is still present in a large proportion of patients and is probably responsible for the increased incidence of cardiovascular, metabolic and central nervous system (CNS) complications that develop in HIV-infected patients [12]. On this background, the introduction of the concept of bacterial translocation during HIV infection has been a very important development [13]. It has added a new player that accounts for immune activation that is not directly related to HIV but rather is the result of HIV infection. It has lent support to the central role the gastrointestinal tract and its associated lymphoid tissue play in the pathogenesis of HIV infection. And not less important, it has introduced new possibilities for treatment that may eventually affect the course of chronic HIV infection [14]. The hallmark of bacterial translocation during HIV infection is the damage to the intestinal mucosa that is caused in the early phases of HIV infection. This damage results in systemic dissemination of bacteria and bacterial products, which then cause and drive the immune activation of the host toward these elements. The presence of intestinal mucosal damage during HIV infection has been well documented in HIV-infected humans as well as in the SIV-infected primate models of HIV infection [15–17]. Studies of SIV-infected primates at various stages of the infection have revealed a clear and significant damage to the mucosa very early in the infection and have also demonstrated chronic changes that persist in the mucosa of the virus-infected animals. They have also demonstrated compellingly that such damage does not occur in the naturally infected primates that do not develop the AIDS-like disease [15]. Thus, the presence or absence of gastrointestinal damage seems to be an additional element distinguishing between animals that will or will not develop the AIDS-like disease. At the present time, there are a number of biomarkers that can determine the presence and magnitude of bacterial translocation. The most useful and commonly used is circulating bacterial lipopolysaccharide (LPS) as determined by the limulus amebocyte lysate assay. However, increased serum levels of soluble CD14 (sCD14), EndoCab and circulating bacterial DNA are also in good correlation to bacterial translocation [17–19]. In this issue of the Journal, Marchetti et al.[20] report on the use of three of these biomarkers (i.e. circulating LPS, sCD14 and EndoCab) in predicting HIV disease progression. They demonstrate that circulating LPS is a very potent predictor of disease progression during the first years of the infection and independently of CD4 cell and HIV viral load. They suggest that circulating LPS should, therefore, be considered as a useful biomarker for HIV monitoring and evaluation in clinical trials. Although earlier studies have shown strong correlation of disease progression to other markers of immune activation, most notably cellular markers of activation-CD38 and HLA-DR on CD8, and Ki67 [10,11,21], this study failed to show such correlation. This may be due to the poor condition of the thawed cells used in the study and the importance of doing such assays on fresh cells. The importance of this report is in highlighting the potential impact of bacterial translocation on disease progression, in driving the immune activation and in the use of circulating LPS as a simple serum biomarker to monitor HIV disease. Such monitoring may become even more useful if new approaches for suppression of the chronic immune activation become available. As intensification of ART has not been effective in suppressing the persistent immune activation [22], new and more effective therapies should be developed for that purpose. As we enter the fourth decade of the AIDS epidemic, it is evident that one of the biggest challenges that AIDS medicine faces is to overcome this persistent chronic immune activation that probably accounts for the increased mortality and early development of cardiovascular, metabolic and CNS chronic diseases [12,23–26]. Though bacterial translocation has been demonstrated in both humans and primates infected with HIV and SIV, respectively, very little is known about the effects of other coinfections, and particularly infections involving the gastrointestinal tract, on this phenomenon. The neglected tropical diseases, and particularly helminth and schistosomal infections, are extremely common in most developing countries and affect very large populations [27]. As they reside and involve the gastrointestinal mucosa, they may cause varying degrees of mucosal damage and bacterial translocation, which can then induce chronic immune activation [28–30]. We have previously demonstrated that helminth-infected people have severe and chronic immune activation in the absence of HIV infection [9,31]. We have also suggested that such immune activation makes the host more susceptible to HIV infection and less able to cope with it [5]. Some recent studies on primates have lent support to our hypothesis, demonstrating that schistosoma-infected primates had higher simian HIV (SHIV) viral loads when infected with SHIV and were also much more susceptible to such infection in comparison with schistosoma-noninfected animals [32,33]. Taken together, these studies and that of Giorgi et al.[20] clearly demonstrate the importance of measuring bacterial translocation as a potent and useful biomarker for disease progression and continued immune activation. They also highlight the importance of the gastrointestinal tract in the pathogenesis of HIV infection and lend further support for the urgent need to study the histopathology and immunology of the gastrointestinal tract in diseases affecting the gastrointestinal tract, and particularly in the developing countries where neglected tropical diseases are so widespread and the AIDS epidemic is still spreading. Lastly, they also demonstrate the importance of developing new approaches for suppressing bacterial translocation [1] and hopefully decreasing the potential for the development of the long-term complications of the persistent immune activation in these patients.