Nef exosomes isolated from the plasma of individuals with HIV-associated dementia (HAD) can induce Aβ1–42 secretion in SH-SY5Y neural cells
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In the era of combined antiretroviral therapy (CART), many of the complications due to HIV-1 infection have diminished. One exception is HIV-associated neurocognitive disorder (HAND). HAND is a spectrum of disorders in cognitive function that ranges from asymptomatic disease to severe dementia (HAD). The milder form of HAND has actually remained the same or slightly increased in prevalence in the CART era. Even in individuals who have maintained undetectable HIV RNA loads, viral proteins such as Nef and Tat can continue to be expressed. In this report, we show that Nef protein and nef messenger RNA (mRNA) are packaged into exosomes that remain in circulation in patients with HAD. Plasma-derived Nef exosomes from patients with HAD have the ability to interact with the neuroblastoma cell line SH-SY5Y and deliver nef mRNA. The mRNA can induce expression of Nef in target cells and subsequently increase expression and secretion of beta-amyloid (Aβ) and Aβ peptides. Increase secretion of amyloid peptide could contribute to cognitive impairment seen in HAND.
KeywordsHIV Nef Combination antiretroviral therapy HIV-associated neurocognitive disorders Amyloid Nef
NIMHD G12 MD007602, U54MD008149 NIAID R21AI095150, CFAR P30AI050409 (MP, VB) NINDS/NIH U54NS43049, NIMH/NIH R21MH68173, and NIMHD/NIH U54MD007584 (BS)
Conflict of interest
The authors declare that they have no conflict of interest.
- Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799CrossRefPubMedPubMedCentralGoogle Scholar
- Aqil, M, Naqvi, AR, Mallik, S, Bandyopadhyay, S, Maulik, U, Jameel, S (2014) The HIV Nef protein modulates cellular and exosomal miRNA profiles in human monocytic cells. J Extracell Vesicles 3. doi: 10.3402/jev.v3.23129. eCollection;%2014., 10.
- Churchill MJ, Gorry PR, Cowley D, Lal L, Sonza S, Purcell DF, Thompson KA, Gabuzda D, McArthur JC, Pardo CA, Wesselingh SL (2006) Use of laser capture microdissection to detect integrated HIV-1 DNA in macrophages and astrocytes from autopsy brain tissues. J Neurovirol 12:146–152CrossRefPubMedGoogle Scholar
- Lamers, SL, Poon, AF, McGrath, MS (2011) HIV-1 nef protein structures associated with brain infection and dementia pathogenesis. PLoS One 6:e16659Google Scholar
- Liu X, Shah A, Gangwani MR, Silverstein PS, Fu M, Kumar A (2014) HIV-1 Nef induces CCL5 production in astrocytes through p38-MAPK and PI3K/Akt pathway and utilizes NF-kB, CEBP and AP-1 transcription factors. Sci Rep 4:4450. doi: 10.1038/srep04450
- Luo X, Fan Y, Park IW, He JJ (2015) Exosomes are unlikely involved in intercellular nef transfer. PLoS One 10:e0124436Google Scholar
- Thery C, Amigorena S, Raposo G, Clayton A (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol Chapter 3:Unit 3.22. doi: 10.1002/0471143030.cb0322s30
- Tozzi V, Balestra P, Serraino D, Bellagamba R, Corpolongo A, Piselli P, Lorenzini P, Visco-Comandini U, Vlassi C, Quartuccio ME, Giulianelli M, Noto P, Galgani S, Ippolito G, Antinori A, Narciso P (2005) Neurocognitive impairment and survival in a cohort of HIV-infected patients treated with HAART. AIDS Res Hum Retroviruses 21:706–713CrossRefPubMedGoogle Scholar
- Wang Z, Trillo-Pazos G, Kim SY, Canki M, Morgello S, Sharer LR, Gelbard HA, Su ZZ, Kang DC, Brooks AI, Fisher PB, Volsky DJ (2004) Effects of human immunodeficiency virus type 1 on astrocyte gene expression and function: potential role in neuropathogenesis. J Neurovirol 10 Suppl 1:25–32., 25–32Google Scholar
- Williams KC, Corey S, Westmoreland SV, Pauley D, Knight H, deBakker C, Alvarez X, Lackner AA (2001) Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS. J Exp Med 193:905–915CrossRefPubMedPubMedCentralGoogle Scholar