HSV Research Lab

Keith Jerome, MD, Ph.D.

Our laboratory (lab photo) focuses on the interaction of herpes simplex viruses (HSV) with the infected cell.   Complex viruses such as HSV must take control of normal intra- and inter-cellular processes to ensure their own replication.   Given this, our working hypothesis is that by understanding the mechanisms through which HSV achieves this control, we are likely to gain new insights into fundamental cellular processes.   Currently we are focused on two main effects of HSV in the infected host:

1.   HSV inhibition of host cell apoptosis.   Normally, when cells become infected with viruses, they attempt to undergo apoptosis.   However, HSV encodes at least 2 proteins with anti-apoptotic properties.   Not only do HSV-infected cells not undergo spontaneous apoptosis, but they also become resistant to apoptosis induction by cytotoxic T lymphocytes (CTL).   This appears to constitute a mechanism of HSV immune evasion, since HSV with intact anti-apoptotic genes replicates much better in the face of CTL attack than does virus with impairment of the anti-apoptotic genes.   We have demonstrated that HSV inhibition of apoptosis is dependent upon two proteins, Us3 and gJ.   We are currently evaluating the effect each of these proteins has on the various mechanisms CTL use to induce target cell apoptosis, and the manner in which this determines successful vs. unsuccessful viral replication.   We are also investigating the molecular basis by which gJ acts at the mitochondrion to inhibit apoptosis.

2.   HSV inactivation of CTL.   HSV has several mechanisms with which to blunt the attack of CTL.   As noted above, HSV protects cells from CTL apoptosis.   HSV also blocks the loading of peptide into MHC class I, making infected cells less "visible" to CTL.   We have recently focused on yet another mechanism, in which HSV-infected cells transduce a signal to CTL that renders the CTL incapable of attacking target cells.   These inactivated CTL are not apoptotic, nor are they infected with HSV, and yet they are incapable of responding to any stimulation mediated via the T cell receptor.   Nevertheless, such CTL retain the normal cytolytic machinery, and respond normally to stimulation via phorbol esters.   We have defined at least one viral gene product necessary for this effect.   Our current efforts focus on identifying any additional gene products required, and elucidating the cellular signaling pathways responsible for inactivation of CTL.

Recent publications:

KR Jerome and L Corey.  The danger within.  New England Journal of Medicine.  350: 411-412.  2004.

DD Sloan, G Zahariadis, CM Posavad, N Pate, S Kussick, and KR Jerome.  Cytotoxic T lymphocytes are inactivated by HSV-infected cells expressing a viral protein kinase.  Journal of Immunology.  171: 6733-6741.  2003

KR Jerome, DA Sloan, and MA Aubert.   Measuring T cell-mediated cytotoxicity using antibody to activated caspase 3.  Nature Medicine.   9:4-5. 2003.

KR Jerome, Z Chen, R Lang, MR Torres, J Hofmeister, S Smith, R Fox, CJ Froelich, and L Corey.   Herpes simplex virus and glycoprotein J inhibit caspase activation and apoptosis induced by granzyme B or fas.  Journal of Immunology.   167:3928-3935.   2001.