I came across a review article in Nature Reviews Microbiology this morning, describing recent advances in our understanding of how HIV is spread. The article also allowed me to revisit the role of the Nef gene/protein in HIV pathogenesis. I worked on HIV Nef in the early 1990s in the laboratory of Dr. J. Victor Garcia at St. Jude Children’s Research Hospital.
The name Nef is an abbreviation of “negative factor” It was so named because early experiments suggested that the protein had a negative effect on virus replication. It was soon found that Nef was also a positive virulence factor that contributed to pathogenesis and disease progression in vivo.
The most striking early finding regarding the function of Nef was its ability to cause the removal or downregulation of CD4 from surface of T cells expressing it. The presence of Nef alone was sufficient to produce this effect; no other viral genes were necessary. This led to speculation that the pathogenic role of Nef may result from the downregulation of CD4 expression and/or the disruption of p56Lck signaling in CD4 T cells.
Since then a number of interactions with important host cellular proteins has been discovered, including
- effects on vesicular transport
- effects on signal transduction
- protection of infected cells from lysis by cytotoxic T cells or natural killer cells
- prevention of superinfection
- modification of host cell responses to increase cell survival and thereby increase production of infectious progeny virions.
Now it appears that one of the most significant functions of Nef is to inhibit migration and mobility of HIV-infected cells. For example, Nef-expressing T cells exhibit decreased lymph node homing and decreased extravasation through high endothelial venules (HEVs). Evidence suggests that this effect may be due, at least in part, to interference with actin function in the cytoplasm of infected cells.
One might speculate that the reduced mobility of infected T cells may promote the interaction of infected cells with uninfected target cells thus increasing the likelihood of virus spreading from cell to cell. Further elucidation of the role of Nef in the mobility of infected cells, and what role this plays in cell to cell transmission, and in viral pathogenesis, will require the development and implementation of new in vivo and in vitro techniques such as multi-transgenic mice, intravital microscopy, and 3D tissue and organ cultures systems. Fortunately significant advances in these areas are being made rapidly. █
The review article contains a more detailed description of the role of HIV Nef in motility and migration, as well as advances in our understanding of species-specific host factors and cell to cell transmission of HIV-1. Use the link below to access the article.
Adding new dimensions: towards an integrative understanding of HIV-1 spread.
Fackler OT, Murooka TT, Imle A, and Mempel TR. 2014. Nat Rev Microbiol. Jul 16;12(8):563-74.