We study retroviruses, particularly the metabolism of retroviral cDNA.
Retroviruses have an RNA genome. After the virus enters a cell, the viral enzyme reverse transcriptase copies the RNA into a linear double-stranded cDNA. The viral cDNA is part of a poorly understood complex of viral and host proteins termed the pre-integration complex (PIC). The PIC includes the viral enzyme integrase. The PIC moves to the nucleus where integrase catalyzes the covalent joining of the viral cDNA genome to the host DNA. The integrated viral genome is called the provirus. After integration the viral genome is transcribed and translated by host machinery to generate progeny viruses. Alternatively the provirus may become transcriptionally silent or latent. After integration the viral genome is stable and is able to produce new viruses as long as the cell lives.
DNA Repair & Retroviruses
We have studied the interactions of host DNA repair proteins and the viral cDNA. Cells have many DNA repair pathways specializing in different types of DNA damage. We have found that nucleotide excision repair proteins XPB and XPD defend against retroviral infection. In contrast, lentiviruses pirate the base excision repair pathway to enhance infection. Of course some DNA repair pathways, such as mismatch repair, have no effect on retroviral infection.
Single Molecule Studies and Chromatin Target DNA
How does an integration complex search target DNA for site to perform integration? How does the search happen when DNA is bound by nucleosomes in the context of chromatin? What features of nucleosomes and/or integrase are important for the search? These are key questions we are trying to answer.
CRISPR genome editing of the HIV-1 provirus
A cure for HIV-1 infection is prevented by the stable existence of the latent provirus. Genome editing technologies, such as CRISPR, offer new possibilities to fight this insidious viral infection.