Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients.
Elevated plasma lipopolysaccharide (LPS), an indicator of microbial translocation from the gut, is a likely cause of systemic immune activation in chronic HIV infection. LPS induces monocyte activation and trafficking into brain, which are key mechanisms in the pathogenesis of HIV-associated dementia (HAD). To determine whether high LPS levels are associated with increased monocyte activation and HAD, we obtained peripheral blood samples from AIDS patients and examined plasma LPS by Limulus amebocyte lysate (LAL) assay, peripheral blood monocytes by FACS, and soluble markers of monocyte activation by ELISA. Purified monocytes were isolated by FACS sorting, and HIV DNA and RNA levels were quantified by real time PCR. Circulating monocytes expressed high levels of the activation markers CD69 and HLA-DR, and harbored low levels of HIV compared to CD4(+) T-cells. High plasma LPS levels were associated with increased plasma sCD14 and LPS-binding protein (LBP) levels, and low endotoxin core antibody levels. LPS levels were higher in HAD patients compared to control groups, and were associated with HAD independently of plasma viral load and CD4 counts. LPS levels were higher in AIDS patients using intravenous heroin and/or ethanol, or with Hepatitis C virus (HCV) co-infection, compared to control groups. These results suggest a role for elevated LPS levels in driving monocyte activation in AIDS, thereby contributing to the pathogenesis of HAD, and provide evidence that cofactors linked to substance abuse and HCV co-infection influence these processes.
Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, United States of America.
Petronela
P
Ancuta
Anupa
A
Kamat
Kevin J
KJ
Kunstman
Eun-Young
EY
Kim
Patrick
P
Autissier
Alysse
A
Wurcel
Tauheed
T
Zaman
David
D
Stone
Megan
M
Mefford
Susan
S
Morgello
Elyse J
EJ
Singer
Steven M
SM
Wolinsky
Dana
D
Gabuzda
D015526:AIDS Dementia Complex / Q000276:immunology*; D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002469:Cell Separation; D004279:DNA, Viral / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006678:HIV / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D008070:Lipopolysaccharides / Q000097:blood; D008213:Lymphocyte Activation; D009000:Monocytes / Q000276:immunology*; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000097:blood; D014779:Virus Replication
D004279:DNA, Viral; D008070:Lipopolysaccharides; D012367:RNA, Viral