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PMID: 15767427 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Human Immunodeficiency virus type 1 Nef potently induces apoptosis in primary human brain microvascular endothelial cells via the activation of caspases.

Journal of virology ·Vol. 79 ·No. 7 ·2005-04-00 ·Pages 4257-69

Acheampong EA, Parveen Z, Muthoga LW, Kalayeh M, Mukhtar M, Pomerantz RJ

Abstract

The lentiviral protein Nef plays a major role in the pathogenesis of human immunodeficiency virus type I (HIV-1) infection. Although the exact mechanisms of its actions are not fully understood, Nef has been shown to be essential for the maintenance of high-titer viral replication and disease pathogenesis in in vivo models of simian immunodeficiency virus infection of monkeys. Nef has also been suggested to play a pivotal role in the depletion of T cells by promoting apoptosis in bystander cells. In this context, we investigated the ability of extracellular and endogenously expressed HIV-1 Nef to induce apoptosis in primary human brain microvascular endothelial cells (MVECs). Human brain MVECs were exposed to baculovirus-expressed HIV-1 Nef protein, an HIV-1-based vector expressing Nef, spleen necrosis virus (SNV)-Nef virus (i.e., SNV vector expressing HIV-1 Nef as a transgene), and the HIV-1 strain ADA and its Nef deletion mutant, ADADeltaNef. We observed that ADA Nef, the HIV-1 vector expressing Nef, and SNV-Nef were able to induce apoptosis in a dose-dependent manner. The mutant virus with a deletion in Nef was able to induce apoptosis in MVECs to modest levels, but the effects were not as pronounced as with the wild-type HIV-1 strain, ADA, the HIV-1-based vector expressing Nef, or SNV-Nef viruses. We also demonstrated that relatively high concentrations of exogenous HIV-1 Nef protein were able to induce apoptosis in MVECs. Gene microarray analyses showed increases in the expression of several specific proapoptotic genes. Western blot analyses revealed that the various caspases involved with Nef-induced apoptosis are processed into cleavage products, which occur only during programmed cell death. The results of this study demonstrate that Nef likely contributes to the neuroinvasion and neuropathogenesis of HIV-1, through its effects on select cellular processes, including various apoptotic cascades.

MeSH Terms
Apoptosis Blotting, Western Brain/blood supply,virology Caspases/metabolism Cells, Cultured Endothelial Cells/physiology,virology Enzyme Activation Gene Deletion Gene Products, nef/genetics,metabolism Genetic Vectors HIV-1/pathogenicity Humans Oligonucleotide Array Sequence Analysis RNA, Messenger/analysis nef Gene Products, Human Immunodeficiency Virus
Chemicals
Gene Products, nef RNA, Messenger nef Gene Products, Human Immunodeficiency Virus Caspases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Acheampong Edward A
Center for Human Virology and Biodefense, Division of Infectious Diseases and Environmental Medicine, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Parveen Zahida
Muthoga Lois W
Kalayeh Mehrnush
Mukhtar Muhammad
Pomerantz Roger J
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.79.7.4257-4269.2005
Published
2005-04-00
Pages
4257-69
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC1061575
Subset
IM
Grants
NIAID NIH HHS · AI46149 · United States
NINDS NIH HHS · NS044513 · United States
NIAAA NIH HHS · R21 AA013849 · United States
NIAAA NIH HHS · AA13849 · United States
NINDS NIH HHS · R01 NS041864 · United States
NIAID NIH HHS · R01 AI046149 · United States
NINDS NIH HHS · R01 NS044513 · United States
NINDS NIH HHS · NS41864 · United States
External Links
PubMed source DOI: 10.1128/JVI.79.7.4257-4269.2005 PMC Full Text View journal details
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