Age-dependent molecular alterations in the autophagy pathway in HIVE patients and in a gp120 tg mouse model: Reversal with beclin-1 gene transfer

Department of Pathology, University of California San Diego, La Jolla, CA, 92093, USA.
Journal of NeuroVirology (Impact Factor: 2.6). 01/2013; 19(1). DOI: 10.1007/s13365-012-0145-7
Source: PubMed


Aged (>50 years old) human immunodeficiency virus (HIV) patients are the fastest-growing segment of the HIV-infected population in the USA and despite antiretroviral therapy, HIV-associated neurocognitive disorder (HAND) prevalence has increased or remained the same among this group. Autophagy is an intracellular clearance pathway for aggregated proteins and aged organelles; dysregulation of autophagy is implicated in the pathogenesis of Parkinson's disease, Alzheimer's disease, and HAND. Here, we hypothesized that dysregulated autophagy may contribute to aging-related neuropathology in HIV-infected individuals. To explore this possibility, we surveyed autophagy marker levels in postmortem brain samples from a cohort of well-characterized <50 years old (young) and >50 years old (aged) HIV+ and HIV encephalitis (HIVE) patients. Detailed clinical and neuropathological data showed the young and aged HIVE patients had higher viral load, increased neuroinflammation and elevated neurodegeneration; however, aged HIVE postmortem brain tissues showed the most severe neurodegenerative pathology. Interestingly, young HIVE patients displayed an increase in beclin-1, cathepsin-D and light chain (LC)3, but these autophagy markers were reduced in aged HIVE cases compared to age-matched HIV+ donors. Similar alterations in autophagy markers were observed in aged gp120 transgenic (tg) mice; beclin-1 and LC3 were decreased in aged gp120 tg mice while mTor levels were increased. Lentivirus-mediated beclin-1 gene transfer, that is known to activate autophagy pathways, increased beclin-1, LC3, and microtubule-associated protein 2 expression while reducing glial fibrillary acidic protein and Iba1 expression in aged gp120 tg mice. These data indicate differential alterations in the autophagy pathway in young versus aged HIVE patients and that autophagy reactivation may ameliorate the neurodegenerative phenotype in these patients.

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Available from: Edward Rockenstein, Dec 18, 2013
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    • "Kong). Wang et al., 2012; Fields et al., 2013; Meng et al., 2013; Torresilla et al., 2013). HIV-1 may affect the process of autophagy through various virus proteins. "
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    Journal of Virological Methods 09/2014; 209. DOI:10.1016/j.jviromet.2014.09.012 · 1.78 Impact Factor
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    • "However, both aged and young HIV subjects with HIVE exhibited increased GFAP and Iba-1 immunostaining and decreased MAP-2 as compared to subjects without HIVE. In addition, there were also differences in the levels of autophagy related proteins in brain tissues samples from young and aged HIVE subjects (Fields et al. 2013). As HIV becomes a more manageable chronic disease, the list of co-morbidities increases and points to the importance of characterizing the differences in brainrelated functions among young and aged HIV + individuals. "
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