Role of HIV in amyloid metabolism

Abstract

HIV infection has changed from an acute devastating disease to a more chronic illness due to combination anti-retroviral treatment (cART). In the cART era, the life expectancy of HIV-infected (HIV+) individuals has increased. More HIV + individuals are aging with current projections suggesting that 50% of HIV + individuals will be over 50 years old by 2015. With advancing age, HIV + individuals may be at increased risk of developing other potential neurodegenerative disorders [especially Alzheimer's disease (AD)]. Pathology studies have shown that HIV increases intra and possibly extracellular amyloid beta (Aβ42), a hallmark of AD. We review the synthesis and clearance of Aβ42; the effects of HIV on the amyloid pathway; and contrast the impact of AD and HIV on Aβ42 metabolism. Biomarker studies (cerebrospinal fluid AB and amyloid imaging) in HIV + participants have shown mixed results. CSF Aβ42 has been shown to be either normal or diminished in with HIV associated neurocognitive disorders (HAND). Amyloid imaging using [(11)C] PiB has also not demonstrated increased extracellular amyloid fibrillar deposits in HAND. We further demonstrate that Aβ42 deposition is not increased in older HIV + participants using [(11)C] PiB amyloid imaging. Together, these results suggest that HIV and aging each independently affect Aβ42 deposition with no significant interaction present. Older HIV + individuals are probably not at increased risk for developing AD. However, future longitudinal studies of older HIV + individuals using multiple modalities (including the combination of CSF markers and amyloid imaging) are necessary for investigating the effects of HIV on Aβ42 metabolism.

Figure 1

Purported pathways for amyloid accumulation in the HIV infected brain. After HIV enters past the blood brain barrier, a chronic state of viral replication causes an upregulation of the amyloidogenic pathology through the following mechanisms. 1) Infected microglia release pro-inflammatory cytokines; Tumor Necrosis Factor alpha (TNFα) & Interleukin 1-beta (IL-1b) that up regulate β (BACE), and γ (gamma) secretases and lead to increases in Aβ42. 2) HIV nef proteins within and around infected astrocytes cause upregulation of Aβ42 leading to accumulation of chemokine ligand-2 (CCL2). 3) Once Aβ42 is invaginated into an endolysosome, HIV tat protein directly inhibits the activity of neprilysin from degrading the amyloid oligomers into inert fragments. These amyloid monomers can then coalesce into intracellular and extracellular oligomers and plaques. 4) HIV proteins can cause the caveolar transport of Aβ42 across the endothelial cells using the receptor for advanced glycation end products (RAGE). 5) HIV indirectly reduces the efflux of Aβ42 by lipoprotein receptor protein (LRP-1).

Figure 2

Regional and mean cortical specific value uptake ratios (SUVR) for HIV infected (HIV+) (red) and HIV− controls (gray). A. SUVR in the gyrus rectus, lateral temporal, cingulate, caudate, precuneus, occipital, prefrontal, and parietal were similar for both groups. Average values were lower than known thresholds for any region of interest (ROI). B. Mean cortical SUVR for the two groups were similar. Average SUVR ratios were less than established amyloid positive threshold criteria (>1.52 arbitrary units) shown as the blue line.

Figure 3

Effects of aging on mean cortical SUVR in HIV+ and HIV− individuals. An increase in mean cortical SUVR was seen with aging for both groups but values did not exceed threshold criteria (>1.52). The slopes for HIV+ and HIV− individuals were 0.0028/year and 0.0025/year, respectively. No significant differences, or interactions were found between groups (p=0.86). Average SUVR ratios for both groups were less than established amyloid positive threshold criteria (>1.52 arbitrary units) shown as the blue dotted line.