Inadequate Clearance of Translocated Bacterial Products in HIV-Infected Humanized Mice

PLoS Pathogens

Stephan Regenass¹  Roberto F. Speck²  Stefan Baenziger²  Marc Nischang²  Ursula Hofer²  Erika Schlaepfer²  David Nadal³  Reto Schwendener⁴  Werner Kempf⁵ 

[1] Division of Clinical Immunology, University Hospital Zurich, Zurich, Switzerland;Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland;Experimental Infectious Diseases and Cancer Research, Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital Zurich, Zurich, Switzerland;Institute of Molecular Cancer Research, University Zurich, Zurich, Switzerland;Kempf and Pfaltz Histological Diagnostics, Zurich, Switzerland

关键词: HIV infections;    Mouse models;    Macrophages;    Gastrointestinal tract;    T cells;    Cytotoxic T cells;    Phagocytosis;    HIV;   

DOI  :  10.1371/journal.ppat.1000867

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Bacterial translocation from the gut and subsequent immune activation are hallmarks of HIV infection and are thought to determine disease progression. Intestinal barrier integrity is impaired early in acute retroviral infection, but levels of plasma lipopolysaccharide (LPS), a marker of bacterial translocation, increase only later. We examined humanized mice infected with HIV to determine if disruption of the intestinal barrier alone is responsible for elevated levels of LPS and if bacterial translocation increases immune activation. Treating uninfected mice with dextran sodium sulfate (DSS) induced bacterial translocation, but did not result in elevated plasma LPS levels. DSS-induced translocation provoked LPS elevation only when phagocytic cells were depleted with clodronate liposomes (clodrolip). Macrophages of DSS-treated, HIV-negative mice phagocytosed more LPS ex vivo than those of control mice. In HIV-infected mice, however, LPS phagocytosis was insufficient to clear the translocated LPS. These conditions allowed higher levels of plasma LPS and CD8+ cell activation, which were associated with lower CD4+/CD8+ cell ratios and higher viral loads. LPS levels reflect both intestinal barrier and LPS clearance. Macrophages are essential in controlling systemic bacterial translocation, and this function might be hindered in chronic HIV infection.

【 授权许可】

CC BY