a number of tumors from inbred animals such as mice and chickens show associated

Question

a number of tumors from inbred animals such as mice and chickens show associated retroviruses. How do you think they affect gene expression in these animals such that it results in cancer? Propose experiments to test your hypothesis.

Explanation / Answer

lab studies 2 different types of viruses, retroviruses like mouse mammary tumor virus (MMTV) and murine leukemia virus (MLV) which cause cancer in mice, and the new world arenaviruses, which cause hemorrhagic fever in humans. The genetics of susceptibility is easily studied with naturally-occurring pathogens in inbred and genetically-manipulated mice. MMTV is an endemic oncogenic retrovirus that has been an infectious agent in mice for > 20 million years, while MLV has been in mice ~ 3 million years. Infectious MMTV is passed from mothers to offspring through milk and first spreads in lymphoid cells before infecting mammary epithelial cells; MLV is probably also milk-transmitted. These viruses thus serve as models for the human milk-borne retroviruses HIV-1 and HTLV1. MMTV causes breast cancer and MLV causes lymphomas when the viral genome inserts next to cellular oncogenes by activating their expression. Our studies focus on understanding the mechanisms that determine susceptibility to MMTV infection and virus-induced mammary tumors and we have identified a number of genes and mechanisms that confer resistance to infection by MMTV and MLV. Genes of the immune system play a major role in susceptibility to infection, and one gene which we recently discovered is involved in the control of MMTV and MLV infection is Apobec3. All mammals encode Apobec3 genes which play a role in intrinsic cellular immunity to a number of viruses, including human immunodeficiency virus type 1. APOBEC3 proteins are packaged into virions and inhibit retroviral replication in newly infected cells, at least in part by deaminating cytosine on the negative strand DNA intermediates. We found that mouse APOBEC3 protein is packaged into MMTV and MLV particles in vitro and dramatically reduces viral titers. Most importantly, APOBEC3 knockout mice are more susceptible to MMTV and MLV infection compared to their wild type littermates. These findings indicate that the APOBEC3 provides protection to mice against retroviral infection and represent the first demonstration that it functions during retroviral infection in vivo. We are currently studying how genetic variation in the mouse APOBEC3 genes affects their ability to inhibit infection and whether APOBEC3 can be used as an anti-retroviral therapeutic target

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