John Guatelli

Affiliation: UCSD SOM

Associate Professor of Medicine

jguatelli@ucsd.edu
Phone: (858)552-8585 ext 7439

Biography

Dr. Guatelli graduated from the University of Colorado, Boulder and went on to receive his M.D. and Infectious Disease training from UCSD.

Research Summary

In my lab, we are primarily studying a single gene of the human immunodeficiency virus (HIV-1) named nef. The name of this gene is an acronym for "negative factor," but in fact nef is negative only for the host. In the absence of nef, HIV-1 seems much less efficient at causing AIDS. The Nef protein is relatively small and associates with the cytoplasmic leaflet of cellular membranes. There, it influences the transport of membranes and of membrane- associated proteins. This has at least two consequences: 1) HIV-1 infected cells become relatively hidden from the immune system, because the molecules that would flag the cells as infected (class I MHC) are removed from the cell-surface; and 2) the infectivity of the virus particle (how efficient it is at establishing a new infection) is increased. We are interested in understanding the precise mechanisms of these effects. We and other labs have identified so-called "sorting motifs" in Nef. These sequences interact with cellular proteins that coat transport vesicles, triggering the formation of the vesicles and determining their selective inclusion of proteins. (We study with respect to Nef a subset of coat proteins known as "adaptor protein complexes"). Recently, we also found that Nef mimics or overrides a cellular protein that regulates these coat proteins, ARF1. Currently, we are using a variety of techniques that measure protein-protein interactions, including microscopy, to test hypotheses regarding Nef's mechanism of action. In forming our hypotheses, we take advantage of ongoing progress in the cell biology of membrane- transport. Finally, we need to relate these ideas to the mechanism by which Nef makes HIV- 1 more infectious. Here, we are testing the hypothesis that Nef targets viral assembly to specific membrane domains; these domains may give the HIV-1 virus an envelope that is better able to fuse with and enter into cells.

Figure: This picture shows cells that express Nef on the left, and the same cells are in the middle panel but the stain shows class I MHC. In cells that express Nef, the class I MHC becomes concentrated in an area next to the nucleus. In many places Nef and class I MHC are very closely related; possibly they are within the same vesicles. This can be seen in the right panel where Nef is colored green and class I MHC is red; where the two overlap becomes yellow.

References

References From PubMed (NCBI)