Several prior blog posts have covered the issue of microbial translocation (the leaking of normally friendly gut bacteria into systemic circulation) in people with HIV. There is now a considerable body of evidence that microbial translocation occurs in chronic HIV infection, but the mechanism remains unclear. The original paper by Jason Brenchley and colleagues suggested that gut CD4 T cell depletion by HIV during acute infection was to blame, but there was no evidence of microbial translocation until later in the progression of disease. The standard measure of microbial translocation is plasma levels of lipopolysaccharide (LPS), and Brenchley et al suggested that anti-LPS antibodies present in early infection effectively mopped up systemic LPS and only when these antibodies waned did levels become detectable.
However, a subsequent mouse study raised the possibility that there might be a connection between loss of naïve CD4 T cells – which happens slowly but progressively as HIV infection advances - and microbial translocation. It turns out that this has been a longstanding observation in the mouse literature, with a 1980 paper documenting microbial translocation in mice bred to lack a thymus, which could be ameliorated when the mice were given thymic grafts.
In the new issue of the Journal of Infectious Diseases, Philip Lee from Irini Sereti’s lab at NIAID sheds further light on the issue with a study of microbial translocation in individuals with idiopathic CD4 T cell lymphopenia (ICL), which is characterized by low CD4 and CD8 T cell levels in the absence of a known cause. In the early years of the HIV epidemic, cases of ICL were briefly a source of controversy due to claims that they represented AIDS without HIV. Studies have since made clear the significant differences between ICL and AIDS: there is no CD8 T cell activation in ICL, whereas the level of CD8 T cell activation is the single strongest predictor of disease progression in HIV infection. CD8 T cell numbers also decline in ICL but increase in HIV until disease becomes very advanced. People with HIV also accumulate both CD4 and CD8 T cell responses to the protein products of all nine HIV genes, such that 20% or more of all memory CD8 T cells can be shown to be HIV-specific by interferon gamma ELISPOT in individuals with an AIDS diagnosis (HIV-specific immune responses are of course entirely absent in ICL).
Lee and colleagues conducted their study to explore whether ICL is associated with microbial translocation. Eleven individuals with ICL were enrolled, along with ten HIV-infected individuals not on ART and 8 HIV-negative healthy controls. Confirming prior results, CD8 counts were significantly elevated in people with HIV compared to controls, while CD8 counts in participants with ICL were significantly lower than controls. CD8 T cell activation was also significantly elevated in HIV infection, but not in controls or individuals with ICL.
The novel and intriguing finding of the study was that plasma LPS levels were significantly elevated – to a similar extent - in both HIV infection and ICL compared to controls. In people with HIV there was a significant association between LPS levels and the percentage of naïve CD4 T cells (r=-0.68; p=.035) but this relationship was not seen in ICL. The researchers also found a significant correlation between the percentage of proliferating CD4 T cells (as measured by Ki67 expression) and LPS levels in ICL (r=-0.88;p=.003), but not in participants with HIV.
The discussion section of the paper cites murine studies indicating that gut bacteria antigens can contribute to lymphopenia-induce CD4 T cell proliferation, and notes that “in individuals with CD4 lymphopenia, including HIV-infected individuals, translocation of microbial products may play an integral role in lymphopenia-induced proliferation and chronic immune activation, or it may simply be the result of CD4 T cell lymphopenia either in the gut or in the lymphoid tissue.”
The finding that the presence of elevated LPS levels is not associated with CD8 T cell activation in ICL is also highlighted. In the initial study of microbial translocation in HIV infection by Jason Brenchley (who is also a co-author on this paper), there was a statistically significant correlation between LPS levels and CD8 T cell activation and systemic LPS was suggested to be playing a causative role. The current study seems to run counter to that, possibility, but, as the authors state, “intermediary steps of the innate immune response may be vastly different in HIV-infected patients.” In other words, it is plausible that the altered immune environment in untreated HIV infection (including factors such as increased antigen-presentation and antigen-presenting cell turnover) could impact the interaction between LPS and CD8 T cells. Alternatively, the researchers acknowledge the possibility that other antigens may be the primary stimulus of CD8 T cell activation in the setting of HIV infection.
Additional studies of the impact of ICL on CD4 T cell numbers in gut and lymphoid tissue should help discern the commonalities and differences in the pathogenesis of microbial translocation in ICL and HIV.
The Journal of Infectious Diseases 2009;199:1664–1670
DOI: 10.1086/598953
MAJOR ARTICLE
Evidence for Translocation of Microbial Products in Patients with Idiopathic CD4 Lymphocytopenia
Philip I. Lee,1 Emily J. Ciccone,1 Sarah W. Read,2 Ava Asher,3 Robert Pitts,1 Daniel C. Douek,3 Jason M. Brenchley,4 and Irini Sereti1
1Laboratory of Immunoregulation, Clinical and Molecular Retrovirology Section, 2Division of AIDS, 3Human Immunology Section, Vaccine Research Center, and 4Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
Translocation of microbial products has been described in chronic human immunodeficiency virus (HIV) infection and correlates with activation of the immune system. We investigated the potential translocation of microbial products in idiopathic CD4 lymphocytopenia (ICL), a rare disorder characterized by low CD4 T cell counts in the absence of HIV infection. Plasma lipopolysaccharide (LPS) levels and T cell activation were measured in a cross‐sectional cohort study of patients with ICL and HIV infection and healthy control subjects. Increases in CD4 T cell proliferation but not CD8 T cell proliferation were observed in patients with ICL. LPS levels were significantly elevated both in patients with ICL and in patients with HIV infection, and they were strongly correlated with the proportion of proliferating CD4 T cells in the cohort of patients with ICL (r=0.88;p=.003). The proportions of T helper (Th) 17 and Th1 CD4 cells in peripheral blood were similar between patients with ICL, patients with HIV infection, and control subjects. These findings suggest a potential association of translocation of microbial products with perturbed CD4 T cell homeostasis in individuals with CD4 lymphopenic states other than HIV infection.
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