Herpes Simplex Virus Inhibition of CTL-Induced Apoptosis

Keith Jerome, MD, PhD

This laboratory research project will evaluate the ability of HSV to inhibit CTL-induced apoptosis. The lifelong persistence of HSV, in spite of measurable virus-specific immune responses, suggests that HSV has evolved effective strategies to avoid the host immune response. One such strategy, demonstrated by these investigators, is that HSV infection causes downregulation of MHC class I expression on infected cells thereby reducing the effectiveness of HSV-specific CTL. Preliminary studies in this project have shown that HSV-1 inhibits the oligonucleosomal DNA fragmentation characteristic of apoptosis making infected cells resistant to apoptosis induced by some CTL. HSV-1 infection was also shown to have no effect on the membrane manifestations of apoptosis. The investigators hypothesize that inhibition of apoptotic DNA fragmentation may be an important means for immune evasion by HSV, and that abrogation or reduction of this inhibitory effect could form the basis of novel therapeutic strategies for HSV infection.

The specific aims of this study are to:

1. Determine if HSV-2 strains can mediate an anti-apoptotic effect as has been shown for HSV-1.
2. Identify the HSV-1 and HSV-2 genes that mediate the anti-apoptotic effect. HSV-1 and HSV-2 gene expression will be limited to individual transcription classes followed by analysis of HSV deletion mutants.
3. Define the cellular targets for each HSV anti-apoptotic gene. Putative HSV-1 and HSV-2 genes will be identified by the yeast two-hybrid system.
4. Determine the ability of HSV to interfere with different apoptosis-inducing mechanisms of CTL.

These studies will provide new and fundamental insights into the mechanisms by which HSV evades the host immune response. The research will also provide the basis necessary for evaluating modulation of the HSV anti-apoptotic effect as a possible therapeutic strategy.

Report courtesy of Anna Marie Beckmann

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Recent Publications

• Jerome KR, Tait JF, Koelle DM, Corey L. Herpes simplex virus type 1 renders infected cells resistant to CTL-induced apoptosis. J Virol 1998; 72:436-41.