Rahul M. Kohli, MD/PhD
Our laboratory focuses on DNA modifying enzymes, particularly those used to generate genomic diversity. We utilize a broad array of approaches, including biochemical characterization of enzyme mechanisms, chemical synthesis of enzyme probes, and biological assays spanning immunology and virology to study this central tactic in the constant battle between our immune system and pathogens.
From the host immune perspective, the generation of genomic diversity is used as both a defensive and an offensive weapon. On the one hand, host mutator enzymes such as Activation-Induced Cytidine Deaminase (AID) seed diversity in the adaptive immune system by introducing targeted mutations into the immunoglobulin locus that result in high affinity antibodies (somatic hypermutation) or altered isotypes (class switch recombination). Related deaminases of the innate immune system can directly attack retroviral threats by garbling the pathogen genome through mutation, as accomplished by the deaminase APOBEC3G, which restricts infection with HIV. Immune mutator enzymes, however, also pose a risk to the host, as overexpression or dysregulation have been associated with oncogenesis.
From the pathogen perspective, alteration in key antigenic determinants at a rate that outpaces immune responses is a potent means for evasion. Further, rapid mutation may allow for the development of resistance to antimicrobials.
Our research program aims to understand mutator enzymes and pathways in the immune system and pathogens. We further aim to harness these diversity-generating systems for directed evolution of proteins. Additionally, we apply chemical biology to decipher and target these pathways, to impede the development of multidrug-resistance in pathogens or prevent the neoplastic transformations that can result from genomic mutation.
Kohli RM. (2010) The chemistry of a dynamic genome. Nat Chem Biol. 6:866-8.
Kohli RM, Maul RW, Guminski AF, McClure RL, Gajula KS, Saribasak H, McMahon MA, Siliciano RF, Gearhart PJ, Stivers JT. (2010) Local sequence targeting in the AID/APOBEC family differentially impacts retroviral restriction and antibody diversification. J Biol Chem. 285:40956-64.
Kohli RM, Abrams SR, Gajula KS, Maul RW, Gearhart PJ, Stivers JT. (2009) A portable hotspot recognition loop transfers sequence preferences from APOBEC family members to activation-induced cytidine deaminase. J. Biol. Chem. 284: 22898-22904.
McMahon MA, Siliciano JD, Lai L, Liu JO, Stivers JT, Siliciano RF, Kohli RM. (2008) The Anti-Herpetic Drug Acyclovir Inhibits HIV Replication and Selects the Reverse Transcriptase V75I Multi-Drug Resistance Mutation. J. Biol. Chem. 283: 31289-31293
Kohli RM, Walsh CT, Burkart MD. (2002) Biomimetic synthesis and optimization of cyclic peptide antibiotics. Nature 418:658-661.
Rahul M. Kohli
Assistant Professor of Medicine and Biochemistry & Biophysics
M.D., 2004, Harvard Medical School
Ph.D., 2004, Harvard Medical School
(Biochemistry and Molecular Pharmacology)
502B Johnson Pavilion
Lab: 509 Johnson Pavilion