The genetics of susceptibility to virus infection is easily studied with naturally-occurring pathogens in inbred and genetically-manipulated mice. We use MMTV and MLV, two endemic retroviruses that have infected mice for millions of years, to study the interplay between host and virus. These viruses also serve as models for the human milk-borne retroviruses HIV-1 and HTLV1.

Recently, the lab has focused on host intrinsic immune factors that restrict virus infection by interacting with reversed-transcribed viral DNA, including APOBEC3 and novel and known host sensors of cytosolic viral DNA. APOBEC3 proteins are packaged into virions and inhibit replication of HIV as well as murine retroviruses in newly infected cells, by deaminating cytosine on negative strand DNA intermediates, and by inhibiting reverse transcriptase. We found that APOBEC3 knockout mice are more susceptible to MMTV and MLV infection than their wild type littermates, providing the first demonstration that it functions during retroviral infection in vivo. We also created transgenic mice expressing human APOBEC3 proteins that we are using to test novel anti-retroviral therapies.Most recently, using mice with naturally occurring genetic polymorphisms, mutant or knockout alleles of cytosolic sensors of viral DNA, we showed that both APOBEC3 and nucleic acid sensing play important roles in vivo to reduce viral load. These studies underscore the importance of the multiple layers of protection afforded by host factors.

The lab also studies new world hemorrhagic fever arenaviruses like Junín virus. These viruses are endemic in new world rodents in South America and spread to humans via aerosolization. We have identified novel host molecules involved in Junín virus entry, as well as different host genes that confer resistance or susceptibility to infection. These studies will help us identify molecules involved in cell- and disease-tropism, as well as to develop new anti-viral therapies.

PhD, Princeton University