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Study Suggests HIV Itself Unleashes Body-Fat-Change Cascade, Gene Study Suggests
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XVII International AIDS Conference
August 3-8, 2008
Mexico City
Mark Mascolini
Results of gene studies imply that HIV-1 infection itself alters metabolic and inflammatory workings in a way that promotes the body-fat changes collectively called HIV-associated lipodystrophy (HALS) [1]. But antiretroviral therapy upsets these functions even more, according to results of a four-group comparison.
Analyzing whole-gene expression in adipose tissue (fat) RNA by two methods, University of Barcelona investigators studied four groups: healthy controls without HIV infection, HIV-infected people who never took antiretrovirals, HIV-infected people who took antiretrovirals but did not have HALS, and HIV-infected, treated people who had HALS. Francesc Villarroya and colleagues matched controls to the HIV-infected groups by age. They looked for genetic markers by whole genome array analysis in RNA extracted from fat tissue and by quantitative RT-PCR of selected genes.
Compared with healthy controls, the antiretroviral-naive HIV group had altered expression of:
- Inflammation-related genes triggered by chemokines and cytokines
- Immunity-related genes controlled by interferon, antibodies, and complement
- Genes related to T-cell activation
Specifically, compared with controls, people with HIV but still naive to antiretrovirals differed significantly in expression of genes that control numerous metabolic and inflammatory functions: complement-mediated immunity (P = 0.015), interferon-mediated immunity (P = 0.016), B-cell and antibody-mediated immunity (P = 0.025), T-cell activation (P < 0.001), inflammation mediated by chemokines and cytokines (P = 0.006), fatty acid beta oxidation (P = 0.003), and the TCA cycle of oxidative metabolism (P < 0.001).
Differences in expression of critical genes grew more marked in antiretroviral-treated people without HALS, and worse still in treated people with HALS. Both antiretroviral-treated groups differed from controls in levels of macrophage-mediated immunity (P = 0.011 for people without HALS and P = 0.009 for people with HALS).
Only people with HALS differed significantly from controls in expression of genes controlling MHC-1- and MHC-2-mediated immunity (P = 0.002 and P = 0.010). And only the HALS group differed significantly from controls in genes regulating fatty acid metabolism (P = 0.013), lipid and fatty acid transport (P = 0.015), oxidative phosphorylation (P = 0.035), electron transport (P = 0.016), and apoptosis (P = 0.047).
Even before HIV-infected people start taking antiretrovirals, the investigators concluded, the virus itself "causes early alterations in adipose tissue gene expression, evidenced by induction of a pro-inflammatory status before full-blown macrophage infiltration, and first signs of impaired adipogenesis and lipid metabolism."
Villarroya and colleagues proposed a complex inflammatory cascade beginning with a "first wave" of pro-inflammatory signaling by HIV itself, leading to repression of lipid accretion genes, repression of genes regulating adipocyte differentiation, and activation of lipid catabolism genes. A "second wave" of pro-inflammatory signaling, touched off by antiretroviral therapy, results in enhanced lipid catabolism, impaired adipocyte differentiation, adipocyte apoptosis, systemic metabolic disturbances linked to altered adipokine release, and ultimately lipoatrophy.
One limitation of this kind of analysis, observed antiretroviral toxicity expert Andrew Carr, is that countless factors affect gene expression and it is impossible to balance out their influence in a case-control comparison.
Reference
1. Villarroya F, Guallar JP, Domingo P, et al. Whole genome transcriptomic analysis of adipose tissue from patients at distinct stages of progression of HIV-1/HAART-associated lipodystrophy reveals alterations in inflammation and metabolism due to HIV-1 infection before antiretroviral treatment. XVII International AIDS Conference. August 3-8, 2008. Mexico City. Abstract WEAB0103.
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