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The Body Covers: The 3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV

October 25, 2001

  • Elevated In Vitro Tumor Necrosis Factor a Release from Abdominal Subcutaneous Adipose Tissue (SAT) in HIV-Infected Subjects with Lipodystrophy
    Presented by: Johnson J.A., Albu J.B., He Q., Engelson E.S., Kotler D.P., St. Luke's-Roosevelt Hospital Center, Columbia University, NY


Interest in the potential role of cytokines in lipodystrophy is growing. This interest was first stimulated by the association found in some observational studies with either complete viral suppression, a history of low CD4 and/or lipodystrophy. An association between a range of cytokines such as tumor necrosis factor (TNF), interferons and some interleukins (such as IL-1, -6 and -12) with HIV-related wasting has been previously noted. Other data in HIV patients have indicated that dysregulation of TNFa production may occur in patients on HAART, with some cells (mainly CD8 lymphocytes) continuing to produce high levels of TNFa. In particular, an association with the proportion of TNFa producing CD8 cells and dyslipidemia was noted in one study. Additionally, raised levels of serum TNFa receptor type 2 are associated with both insulin resistance and lipoatrophy and individuals with specific TNFa polymorphisms that promote TNFa production appear more prone to develop lipodystrophy -- underlining the potential for a genetic contribution to risk. TNFa is a known inducer of apoptosis (programmed cell death) in adipocytes, fat release (lipolysis) and may be produced by adipocytes or by T cells located in adipose tissue.

A role for cytokines has been a favored view of Dr. Don Kotler, who presented data on 30 HIV-infected and 10 HIV-negative control individuals who were studied for body composition by whole body MRI and with fat aspiration from the subcutaneous abdominal adipose tissue. These aspirates were then incubated and assayed for glycerol release (to assess lipolysis), TNFa and leptin (the "satiety factor" released by fat cells to regulate food intake and fat mass). Patients with HIV were assessed clinically as either lipodystrophic or lipodystrophy free. However, objective data from MRI scans indicated that the lipodystrophy-free patients had both less subcutaneous adipose tissue (SAT) and less visceral (intraabdominal) adipose tissues (VAT). Those considered as having lipodystrophy were more matched to control patients with regard to total abdominal fat, although the ratio of SAT:VAT tended to be higher in these patients. Greater fat mass alone may mean more TNF and more leptin, as these changes have been reported in obese individuals.

Biopsy data indicated a trend to more glycerol release from SAT in HIV-positive patients, greatest in those considered lipodystrophy free. Importantly, TNFa secretion was significantly higher in SAT from those with lipodystrophy relative to controls and relative to lipodystrophy-free individuals. Use of antiretrovirals (ART) including or excluding protease inhibitors did not associate with TNF release. Leptin release did not differ across groups but was higher in those not receiving ART.

While the study has limitations due to the relative fat mass difference between the lipodystrophy and lipodystrophy-free individuals, several issues are raised. The increased lipolysis (glycerol release) in HIV-positive treated patients is consistent with ART with more fat release. However, the independent association of raised TNFa with clinical lipodystrophy suggests that this pro-lipolytic, pro-apoptotic cytokine may be involved with the pathogenesis of lipodystrophy consistent with previous data. In vitro data also presented during the meeting (Agrawal K.C., Abstract 25) indicated synergistic anti-adipogenic (preventing differentiation of new fat cells) effects when TNFa was added to PIs. Thus, failure to replace lost fat may be accelerated when both elevated TNFa and PIs are present together.




  
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Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.

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