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Microbial Translocation Is a Cause of Systemic Immune Activation in Chronic HIV Infection
Jason Brenchley*1, D Price1, T Schacker2, G Silvestri3, O Lambotte4, A Landay5, L Picker6, M Lederman7, S Deeks8, and D Douek1
1Vaccine Res Ctr, NIAID, NIH Bethesda, MD, US; 2Univ of Minnesota, Minneapolis, US; 3Univ of Pennsylvania, Philadelphia, US; 4Ctr Univ Hosp Bicetre, France; 5Rush Med Coll, Chicago, IL, US; 6Oregon Hlth and Sci Univ, Portland, US; 7Case Western Reserve Univ, Cleveland, OH, US; and 8Univ of California, San Francisco, US
Background: Chronic activation of the immune system is a
hallmark of progressive HIV infection and better predicts disease outcome than
plasma viral load, yet its etiology remains obscure. Several studies suggest
that the integrity of the gastrointestinal immune system is devastated after
the acute phase. This may allow increased translocation of luminal microbial
products and consequently increased systemic immune activation.
Methods: We measured microbial translocation, as
determined by plasma LPS levels, in a cohort of >300 subjects, including
HIV-uninfected individuals, chronically infected individuals before and after
HAART, long-term nonprogressors, as well as simian immunodeficiency virus (SIV)-infected
rhesus macaques and sooty mangabeys. In addition, we measured T-cell
activation, monocyte responsiveness, and plasma levels of several soluble
factors associated with immune activation.
Results: Chronic progressive HIV infection is
associated with increasing levels of microbial translocation across the
gastrointestinal tract, as defined by plasma LPS. Translocated LPS is bioactive in vivo and directly correlates with
several independent aspects of innate and adaptive immune activation. In
addition, low levels of natural anti-LPS antibodies during chronic
HIV-infection were consistently associated with higher levels of immune
activation. HAART only partially reduces microbial translocation. Finally,
while chronically SIV-infected rhesus macaques also exhibit signs of microbial
translocation this does not occur in nonpathogenic SIV infection of sooty
mangabeys.
Conclusions: These studies strongly suggest that
translocation of microbial products from a damaged gastrointestinal tract is an
important cause of immune activation in chronic HIV disease. Moreover, these
data provide novel directions for therapeutic interventions that modify the
consequences of HIV infection. The aim would be to prevent or reduce the
propagation of HIV at mucosal surfaces, to restore the immunological and
epithelial integrity of the mucosal barrier, and to block pathways through
which microbial products cause systemic immune activation.
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