One of the most fascinating thing I found associated with all types of viruses is that they are capable of hijacking cellular machinery with only a few genes. In the case of dengue virus (DENV), it only codes for 7 nonstructural and 3 structural genes. And how these tiny viruses can take over host cells of about 20000-25000 genes is just fascinating. I attended a seminar, called “The ESCRT pathway in HIV budding and cell division” today down at GCIS. It was hosted by Dr. Wesley Sundquist from University of Utah (shown right). And here, I will talk about what the major concepts mentioned in the talk.
According to wikipedia, “ESCRT (endosomal sorting complex required for transport) refers to a series of cytosolic protein complexes called ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III.” There are 3 major roles of ESCRT machinery: (1) multivesicular bodies (MVB) formation, (2) virus budding, and (3) cytokinesis. The MVB formation is important in recycling receptors that are endocytosed into the cells. One of the prime examples is the EGF receptor that gets endocytosed after binding to the EGF molecules. After the EGFR is internalized in the lysosome, it is then localized in the MVB to traffick to the endosomes for ubiquitination, which is then expressed on the cell surface for another round of binding to EGFR. In the case of cytokinesis, ESCRT-III forms a multimer around the midbody between two daughter cells (in other words, it wrap around the junction between two daughter cells). Then, an ATPase interacts with ESCRT-III to facilitate the cleavage and separate the two daughter cells. (it is likely that this ATPase contribute a conformational change to the ESCRT-III proteins, which give rise to enough thermal energy to break apart the junction.
HIV exploits this pinching technique by ESCRT-III to bud off from the host cells. It was shown that the envelope protein, Gag, interacts with ALIX. ALIX then interacts with ESCRT-III, which then Vps4 ATPase comes in to facilitate the pinching. As a result, progeny HIV can then be released from the host cells to continue infect neighboring uninfected cells. In the case of ALIX-depleted (siRNA-ALIX treated) cells (see below), HIV is not able to bud well from the host cell, and there is some distinguishable difference in the envelope of the HIV between the wildtype HIV and ALIX binding site mutant HIV.
Taken together, HIV exploits the cellular cleavage mechanism used for cytokinesis to facilitate its budding from the host.
– Virus exploits cellular pathways to facilitate its replication cycle
– Cellular ESCRT pathway is important for HIV budding.
Fujii et al. Freed, Functional role of Alix in HIV-1 replication, Virology, Volume 391, Issue 2, 1 September 2009, 284-292, J. Virol.
Wollert et al. The ESCRT machinery at a glance. July 1, 2009 J Cell Sci 122, 2163-2166.