Abstract
BackgroundRetroviruses have been observed to bud intracellularly into multivesicular bodies (MVB), in addition to the plasma membrane. Release from MVB is thought to occur by Ca2+-regulated fusion with the plasma membrane.Principal FindingsTo address the role of the MVB pathway in replication of the murine leukemia virus (MLV) we took advantage of mouse models for the Hermansky-Pudlak syndrome (HPS) and Griscelli syndrome. In humans, these disorders are characterized by hypopigmentation and immunological alterations that are caused by defects in the biogenesis and trafficking of MVBs and other lysosome related organelles. Neonatal mice for these disease models lacking functional AP-3, Rab27A and BLOC factors were infected with Moloney MLV and the spread of virus into bone marrow, spleen and thymus was monitored. We found a moderate reduction in MLV infection levels in most mutant mice, which differed by less than two-fold compared to wild-type mice. In vitro, MLV release form bone-marrow derived macrophages was slightly enhanced. Finally, we found no evidence for a Ca2+-regulated release pathway in vitro. Furthermore, MLV replication was only moderately affected in mice lacking Synaptotagmin VII, a Ca2+-sensor regulating lysosome fusion with the plasma membrane.ConclusionsGiven that MLV spreading in mice depends on multiple rounds of replication even moderate reduction of virus release at the cellular level would accumulate and lead to a significant effect over time. Thus our in vivo and in vitro data collectively argue against an essential role for a MVB- and secretory lysosome-mediated pathway in the egress of MLV.
Highlights
Retroviruses such as the murine leukemia virus (MLV) and the human immunodeficiency virus (HIV) have been reported to accumulate in intracellular vesicles, called multivesicular bodies (MVB)
Given that MLV spreading in mice depends on multiple rounds of replication even moderate reduction of virus release at the cellular level would accumulate and lead to a significant effect over time
Our in vivo and in vitro data collectively argue against an essential role for a MVB- and secretory lysosome-mediated pathway in the egress of MLV
Summary
Retroviruses such as the murine leukemia virus (MLV) and the human immunodeficiency virus (HIV) have been reported to accumulate in intracellular vesicles, called multivesicular bodies (MVB). Downregulation of TIP47 as well as Rab blocks HIV release [12,14]. Compelling evidence has recently been reported that retroviral HIV Gag accumulating in MVBs originates from the plasma membrane [15,16,17,18]. Interference with endocytosis blocked the accumulation of HIV Gag at MVBs, yet did not interfere with the release of virus infectivity from cells [16,17]. Retroviruses have been observed to bud intracellularly into multivesicular bodies (MVB), in addition to the plasma membrane. Release from MVB is thought to occur by Ca2+-regulated fusion with the plasma membrane
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