Picture of Dr. Linda Chelico

Dr. Linda Chelico Faculty, Microbiology & Immunology

About Dr. Linda Chelico

Areas of Expertise

HIV restriction factors, DNA deaminases, mutagenesis, enzyme mechanisms

In the News

U of S researchers hope to harness human DNA to fight HIV

Evolution of the arms race

Finding a cure for HIV a balancing act

Research Interests

Retrotransposons and endogenous retroviruses have been genomic parasites in organisms throughout evolution and have contributed to both species evolution and disease. The APOBEC (Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide) family of enzymes present in their earliest form in bony fish acted as a defense to retroelements. Due to expansion of retroelements through evolution there was a corresponding expansion in the APOBEC family. The most recent expansion in placental mammals formed the APOBEC-like 3 (APOBEC3) family in response to ancient pathogenic retroviruses. Humans contain seven APOBEC3 (A3) enzymes (A3A, A3B, A3C, A3D, A3F, A3G, and A3H).

The A3 enzymes act as host restriction factors to inhibit retroelement replication through either RNA binding ability or activity as single-stranded (ss) DNA cytosine deaminases that catalyze the formation of promutagenic uracils. Our lab studies from a biochemical perspective how A3 enzymes restrict the replication of the retrovirus HIV-1.

Restriction of the replication of HIV-1 by A3 enzymes occurs through the deoxycytidine deamination activity of A3 enzymes which results in hypermutated and inactivated viral genomes. HIV can overcome A3 restriction factors by encoding the accessory protein Vif that hijacks the host ubiquitination system to induce polyubiquitination and proteasomal degradation of A3 enzymes.

Inhibition of HIV-1 by A3G that escapes Vif mediated degradation. In an HIV-1 producer cell, the HIV-1 virus infectivity factor (Vif) interacts with the cotranscription factor CBF-β and a cellular ubiquitin ligase complex to become the substrate recognition subunit of an E3 ubiquitin ligase. (1) The Vif-E3 complex recruits an E2 enzyme that transfers ubiquitin molecules to A3G, thereby signaling it for degradation through the proteasome pathway. (2) A3G that escapes this fate, either fortuitously or in the presence of a Vif-defective HIV-1 strain, can enter an assembling virus particle through interactions with RNA (host 7SL RNA or HIV-1 genomic RNA) and the nucleocapsid portion of Gag. Then, A3G travels with the HIV-1 particle to a target cell where it waits for reverse transcription of the HIV-1 genomic RNA to (-)DNA to ensue. A3G, a single-stranded DNA deaminase is able to deaminate cytosine (C) to uracil (U) in (-)DNA, which causes the reverse transcriptase to introduce guanine (G) to adenine (A) mutations upon using uracil-containing (-)DNA as a template to synthesize (+)DNA. This creates a hypermutated and likely inactivated virus. Other A3 enzymes, such as A3D, A3F and A3H, can restrict HIV replication in the same manner, although not all A3 enzymes are equally sensitive to Vif-mediated degradation.
Figure credit: Robin P. Love.

Our lab studies:

(1) The biochemistry of A3 enzymes and how A3 enzymes scan nascently produced single-stranded DNA during HIV reverse transcription for cytosines to deaminate.

(2) The biochemical interface of Vif and A3 enzymes and the biochemical determinants of Vif-mediated degradation of A3 enzymes.

Selected Publications