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Immune Activation and Inflammation Due to Leaking Gut Bacteria Linked to HIV Disease Progression

Microbial translocation, or leakage of bacteria from the gut, is increased in people with HIV and is associated with ongoing immune activation, CD4 cell loss, higher viral load, and progression to AIDS, according to 3 recently published reports. One study found that effective antiretroviral therapy (ART) reduced levels of the bacterial toxin lipopolysaccharide (LPS) to normal levels in HIV positive adults, but a study of HIV-infected children showed that LPS elevation and immune activation persisted even after CD4 cell recovery and viral suppression on ART.

Inflammation and its role in disease progression and non-AIDS conditions has become a growing focus of HIV research in recent years. One trigger of chronic immune activation and inflammation in people with HIV is bacteria -- and the toxic substances they produce -- escaping from the gut when the virus damages the intestinal lining, a process known as microbial translocation.

Lipopolysaccharide

In the first study, published in the July 17, 2010 issue of AIDS, Marius Troseid from the Karolinska Institute in Stockholm and colleagues analyzed plasma levels of high mobility group box-1 protein (HMGB1; a marker of tissue necrosis and immune activation) and LPS (a toxin produced by bacteria that indicates microbial translocation) in people with HIV.

The study included 32 HIV positive participants who responded well to ART and had undetectable viral load after 2 years, as well as ART non-responders, treatment-naive HIV patients, and HIV negative control subjects.

The researchers found that treatment-naive patients had significantly elevated levels of HMGB1 and LPS compared with control subjects. But they observed some notable differences between racial/ethnic groups. LPS levels were higher in African and Asian patients compared with whites. HIV viral load was twice as high in people with elevated LPS, and HMGB1 was above the median. This association was largely driven by Africans, who had a 5-fold increase in viral load in the presence of elevated LPS and HMGB1. After 2 years on effective ART, LPS fell to the same median level as that of the HIV negative control group and HMGB1 also decreased, but these reductions were not seen in ART non-responders.

"The new findings are the association of elevated plasma levels of LPS and HMGB1 with high viral load, as well as the normalized levels of LPS, and the reduction of HMGB1 after 2 years of effective antiretroviral therapy," the study authors concluded. "As LPS and HMGB1 tend to form immunologically active complexes in vitro, we propose that such complexes may be involved in the immune activation and pathogenesis of HIV-1 infection."

LPS and Disease Progression

In the second study, described in a Brief Report in the April 15, 2010 Journal of Infectious Diseases, Salma Nowroozalizadeh from the Swedish Institute for Infectious Disease Control looked at microbial translocation and its associated with HIV disease progression.

An elevated level of microbial translocation, measured by plasma LPS concentration, was found to correlate with progression to AIDS in people with either HIV-1 or HIV-2 (a typically less aggressive strain found primarily in West Africa). LPS concentrations were also correlated with CD4 T-cell count and viral load independent of HIV type. Elevated plasma LPS was linked to impaired innate and mitogen immune responses.

"We suggest that microbial translocation may contribute to loss of CD4+ T-cells, increase in viral load, and defective immune stimuli responsiveness during both HIV type 1 and HIV type 2 infections," the researchers concluded.

Immune Activation in Children

Finally, the third second study, described in the June 1, 2010 issue of AIDS, looked at microbial translocation and immune activation in children with HIV.

Mark Wallet from the University of Florida and colleagues analyzed cellular and soluble plasma biomarkers of inflammation in 33 children perinatally infected with HIV prior to and during 96 weeks of protease inhibitor-based ART and in 14 healthy HIV negative children. The children with HIV experienced CD4 cell reconstitution either with suppressed viral load or rebound of drug-resistant virus.

Systemic immune activation was determined by testing blood lymphocytes (immune cells including T-cells and B-cells) and plasma for soluble CD27, soluble CD14, and tumor necrosis factor. Immune activation markers were analyzed according to viral load, CD4 cell percentage, and LPS level.

The investigators detected evidence of microbial translocation in children from both groups, but in the healthy HIV negative infants this resolved with age. In contrast, LPS and soluble CD14 levels were significantly elevated in all HIV-infected children and persisted even if CD4 cells were fully reconstituted, viral load was optimally suppressed, and lymphocyte activation resolved with ART. Children who had CD4 cell reconstitution but experienced viral rebound on ART continued to exhibit high levels of soluble CD27.

Based on these findings, the study authors concluded, "Microbial translocation in pediatric HIV-1 infection is associated with persistent monocyte/macrophage activation independent of viral replication or T-cell activation."

Investigator affiliations:

Troseid study: Department of Clinical Virology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.

Nowroozalizadeh study: Swedish Institute for Infectious Disease Control, Solna, Sweden; Department of Microbiology, Tumor, and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Infectious Diseases Research Unit, Department of Clinical Sciences, Lund University, Malmo, Sweden; Department of Laboratory Medicine and Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden; Bandim Health Project, INDEPTH Network, Danish Epidemiology Science Centre and National Laboratory for Public Health, Bissau, Guinea-Bissau.

Wallet study: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.

7/13/10

References

M Troseid, P Nowak; J Nystrom, and others. Elevated plasma levels of lipopolysaccharide and high mobility group box-1 protein are associated with high viral load in HIV-1 infection: reduction by 2-year antiretroviral therapy. AIDS 2(11): 1733-1737 (Abstract). July 17, 2010.

S Nowroozalizadeh, F Mansson, Z da Silva, and others. Microbial Translocation Correlates with the Severity of Both HIV-1 and HIV-2 Infections. Journal of Infectious Diseases 201(8): 1150-1154 (Abstract). April 15, 2010.

MA Wallet, CA Rodriguez, L Yin, and others. Microbial translocation induces persistent macrophage activation unrelated to HIV-1 levels or T-cell activation following therapy. AIDS 24(9): 1281-1290 (Abstract). June 1, 2010.