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Untreated HIV Increases Inflammation in Women

Women with untreated HIV infection had different cytokine patterns and higher levels of inflammatory biomarkers than HIV negative WIHS participants, but antiretroviral therapy largely reversed this effect.

A growing body of evidence indicates that many of the detrimental effects of chronic HIV infection may be related to excessive immune activation and ongoing inflammation. Over decades of infection, CD4 T-cells and other immune cells appear to age prematurely and "burn themselves out."

The SMART treatment interruption trial and other studies have shown that consistent antiretroviral therapy (ART) reduces inflammation and its negative effects. Other researchers, however, have found that changes in inflammation and immune activation related to HIV infection persist even among people with undetectable viral load on ART. Some of these changes have been shown to promote HIV replication and disease progression, while others have opposite effects.

As reported in the May 12, 2011, advance online edition of AIDS, Sheila Keating and fellow investigators with the Women's Interagency HIV Study (WIHS) compared the extent and type of cytokine changes in women with and without HIV.

The researchers measured 32 cytokines and related immune biomarkers in a cross-sectional study of WIHS participants in 3 groups: women who responded well to combination ART and had undetectable HIV RNA (n = 17); untreated HIV positive non-controllers (n = 14), and HIV negative women (n = 17). The study population as a whole was predominantly African-American and the median age was approximately 38 years.

Results

  • Several cytokines and chemokines (chemical messengers) showed significant differences between untreated non-controllers and HIV negative participants.
  • Relative to HIV negative women, the untreated HIV positive group had:
  • Elevated IP-10;
  • Elevated tumor necrosis factor-alfa (TNF-alfa);
  • Decreased IL-15;
  • Decreased interleukin 12 (IL-12);
  • Decreased fibroblast growth factor 2 (FGF-2).
  • Overall, biomarker levels among women on ART more closely resembled those of HIV negative women, with the exception of TNF-alfa and FGF-2.
  • In an analysis of the combined HIV positive ART-treated and untreated groups, IP-10 showed a strong positive correlation with viral load and a negative correlation with CD4 T-cell count.
  • The growth factors FGF-2, VEGF, and EGF and all showed a positive correlation only with increased CD4 count.

Based on these findings, the researchers wrote, "Untreated, progress[ive] HIV infection was associated with decreased serum levels of cytokines important in T-cell homeostasis (IL-15) and T-cell phenotype determination (IL-12), and increased levels of innate inflammatory mediators such as IP-10 and TNF-alfa."

"[Highly active antiretroviral therapy] was associated with cytokine profiles that more closely resembled those of HIV uninfected women," they continued. "The distinctive pattern of cytokine levels in the 3 study groups may provide insights into HIV pathogenesis, and responses to therapy."

"While most of the cytokine changes previously described to be elevated or reduced during chronic HIV infection were confirmed in our cohort of women with uncontrolled HIV replication, we did not find significant elevations reported by others in predominantly male populations," the researchers explained in their discussion. "Although median IL-10 levels in our untreated HIV-infected group were nearly 2-fold higher compared to the HIV-negative participants, this difference was not statistically significant. In contrast, median IL-6 and FGF-2 values were lower in the [non-controller] than [the HIV negative] group."

Noting that some researchers have observed other types of cytokine changes in people with early infection, the authors said these differences "highlight the fact that the interaction between HIV and the immune system is likely very different in primary and chronic HIV."

In summary, they concluded, "we found that compared to HIV-negative women, untreated chronic HIV infection was associated with defects in T-cell signaling pathways, coupled with evidence of activation of the innate immune system, and these differences were less apparent or absent in HAART-treated women with undetectable viral load."

Investigator affiliations: Blood Systems Research Institute, San Francisco, CA; Departments of Laboratory Medicine, Pharmacy, and Medicine, University of California, San Francisco, CA; Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Keck School of Medicine of the University of Southern California, Los Angeles, CA; Georgetown University Medical Center, Washington, DC; Albert Einstein College of Medicine, Bronx, NY; SUNY Downstate Medical Center, Brooklyn, NY; Department of Medicine, Stroger Hospital, Chicago, IL; Rush University Medical Center, Chicago, IL.

5/24/11

Reference
SM Keating, ET Golub, M Nowicki, et al (Women's Interagency HIV Study). The effect of HIV infection and HAART on inflammatory biomarkers in a population-based cohort of US women. AIDS (abstract). May 12, 2011 (Epub ahead of print).