MERIT Award Recipient: Laimonis A. Laimins, Ph.D.
Life Cycle of Oncogenic Papillomaviruses
Infection by certain types of human papillomaviruses (HPV) is responsible for the development of 99% of cases of cervical cancer. A vaccine was recently introduced that blocks infection by HPVs and should prevent the development of 70% of cases of cervical cancer in the future. However, this vaccine does not target all HPV types and has no effect on individuals who have already been infected. It will also take several decades for this vaccine to significantly reduce the number of cases of cervical cancer. It is therefore important to understand the pathogenesis of HPV infections and so help to develop effective anti-virals. The long-term objective of this grant is to investigate the mechanisms that regulate the productive life cycle of human papillomaviruses (HPV) in differentiating epithelial cells. Papillomaviruses are small DNA viruses that induce a variety of proliferative lesions in most mammals including humans. Of the 100 types of human papillomaviruses that have been identified, a subset can induce anogenital cancers and these are referred to as the high-risk types (16, 18 31, 33 and 45). Viral infection occurs into stratified epithelial cells and results in an altered pattern of differentiation from that seen in normal cells. The production of viral particles, genome amplification, capsid protein synthesis, and virion assembly is dependent upon differentiation and is restricted to suprabasal cells. My laboratory developed methods to grow high-risk human papillomaviruses in tissue culture using organotypic cultures to induce differentiation. We have gone on to develop methods for genetic analyses of HPV functions. The studies supported by this grant examine the function of several HPV viral proteins during the productive life cycle. The E4 protein is the most highly expressed viral factor and we will determine how it regulates late viral functions. Additional studies will investigate how the E5 protein acts to modulate signaling upon differentiation. Finally, we will determine how activation of a cell death pathway by HPV proteins functions to promote viral replication in differentiating cells. These studies should help to understand the processes regulating the productive viral life cycle and will facilitate the development of anti-viral therapies to treat HPV infections.