Luc Montagnier (1932-2022).

Discoverer of the human immunodeficiency virus.

Mouse APOBEC1 cytidine deaminase can induce somatic mutations in chromosomal DNA.

Background: APOBEC1 (A1) enzymes are cytidine deaminases involved in RNA editing. In addition to this activity, a few A1 enzymes have been shown to be active on single stranded DNA. As two human ssDNA cytidine deaminases APOBEC3A (A3A), APOBEC3B (A3B) and related enzymes across the spectrum of placental mammals have been shown to introduce somatic mutations into nuclear DNA of cancer genomes, we explored the mutagenic threat of A1 cytidine deaminases to chromosomal DNA.

A First-in-Human Phase I Study of INVAC-1, an Optimized Human Telomerase DNA Vaccine in Patients with Advanced Solid Tumors.

Purpose: Human telomerase reverse transcriptase (hTERT) is highly expressed in >85% of human tumors and is thus considered as a good tumor-associated antigen candidate for vaccine development. We conducted a phase I study to investigate the safety, tolerability, clinical response, and immunogenicity of INVAC-1, a DNA plasmid encoding a modified hTERT protein in patients with relapsed or refractory solid tumors.

Patients And Methods: INVAC-1 was either administered by intradermal route followed by electroporation or by Tropis, a needle-free injection system.

A DNA telomerase vaccine for canine cancer immunotherapy.

Telomerase reverse transcriptase (TERT) is highly expressed in more than 90% of canine cancer cells and low to absent in normal cells. Given that immune tolerance to telomerase is easily broken both naturally and experimentally, telomerase is an attractive tumor associated antigen for cancer immunotherapy. Indeed, therapeutic trials using human telomerase peptides have been performed.

Hypoxia-induced human deoxyribonuclease I is a cellular restriction factor of hepatitis B virus.

Numerous human APOBEC3 cytidine deaminases have proven to be, inter alia, host cell restriction factors for retroviruses and hepadnaviruses. Although they can bind to genomic RNA and become encapsidated, they are only catalytically active on single-stranded DNA. As there are many cellular deoxyribonucleases (DNases), we hypothesized that a parallel could be struck between APOBEC3 and DNases.

Genotoxic stress increases cytoplasmic mitochondrial DNA editing by human APOBEC3 mutator enzymes at a single cell level.

Human cells are stressed by numerous mechanisms that can lead to leakage of mitochondrial DNA (mtDNA) to the cytoplasm and ultimately apoptosis. This agonist DNA constitutes a danger to the cell and is counteracted by cytoplasmic DNases and APOBEC3 cytidine deamination of DNA. To investigate APOBEC3 editing of leaked mtDNA to the cytoplasm, we performed a PCR analysis of APOBEC3 edited cytoplasmic mtDNA (cymtDNA) at the single cell level for primary CD4 T cells and the established P2 EBV blast cell line.

Elephant APOBEC3A cytidine deaminase induces massive double-stranded DNA breaks and apoptosis.

The incidence of developing cancer should increase with the body mass, yet is not the case, a conundrum referred to as Peto's paradox. Elephants have a lower incidence of cancer suggesting that these animals have probably evolved different ways to protect themselves against the disease. The paradox is worth revisiting with the realization that most mammals encode an endogenous APOBEC3 cytidine deaminase capable of mutating single stranded DNA.

Strong antigen-specific T-cell immunity induced by a recombinant human TERT measles virus vaccine and amplified by a DNA/viral vector prime boost in IFNAR/CD46 mice.

Cancer immunotherapy is seeing an increasing focus on vaccination with tumor-associated antigens (TAAs). Human telomerase (hTERT) is a TAA expressed by most tumors to overcome telomere shortening. Tolerance to hTERT can be easily broken both naturally and experimentally and hTERT DNA vaccine candidates have been introduced in clinical trials.

The rabbit as an orthologous small animal model for APOBEC3A oncogenesis.

APOBEC3 are cytidine deaminases that convert cytidine to uridine residues. APOBEC3A and APOBEC3B enzymes able to target genomic DNA are involved in oncogenesis of a sizeable proportion of human cancers. While the locus is conserved in mammals, it encodes from 1-7 genes.

Self-cytoplasmic DNA upregulates the mutator enzyme APOBEC3A leading to chromosomal DNA damage.

Foreign and self-cytoplasmic DNA are recognized by numerous DNA sensor molecules leading to the production of type I interferons. Such DNA agonists should be degraded otherwise cells would be chronically stressed. Most human APOBEC3 cytidine deaminases can initiate catabolism of cytoplasmic mitochondrial DNA.

PCR mediated recombination impacts the analysis of hepatitis B Virus covalently closed circular DNA.

Background: The replication of HBV involves the production of covalently closed circular DNA (cccDNA) from the HBV genome through the repair of virion relaxed circular DNA (rcDNA) in the virion. As cccDNA is the transcription template for HBV genomes, it needs to be eliminated from hepatocytes if the eradication of chronic HBV infection is to be achieved. PCR quantitation of cccDNA copy number is the technique of choice for evaluating the efficiency of treatment regimens.

APOBEC3DE Antagonizes Hepatitis B Virus Restriction Factors APOBEC3F and APOBEC3G.

The APOBEC3 locus consists of seven genes (A3A-A3C, A3DE, A3F-A3H) that encode DNA cytidine deaminases. These enzymes deaminate single-stranded DNA, the result being DNA peppered with CG →TA mutations preferentially in the context of 5'TpC with the exception of APOBEC3G (A3G), which prefers 5'CpC dinucleotides. Hepatitis B virus (HBV) DNA is vulnerable to genetic editing by APOBEC3 cytidine deaminases, A3G being a major restriction factor.

Anticancer DNA vaccine based on human telomerase reverse transcriptase generates a strong and specific T cell immune response.

Human telomerase reverse transcriptase (hTERT) is overexpressed in more than 85% of human cancers regardless of their cellular origin. As immunological tolerance to hTERT can be overcome not only spontaneously but also by vaccination, it represents a relevant universal tumor associated antigen (TAA). Indeed, hTERT specific cytotoxic T lymphocyte (CTL) precursors are present within the peripheral T-cell repertoire.

An avian H7N1 gain-of-function experiment of great concern.

Inappropriately named gain-of-function influenza research seeks to confer airborne transmission on avian influenza A viruses that otherwise cause only dead-end infections in humans. A recent study has succeeded in doing this with a highly pathogenic ostrich H7N1 virus in a ferret model without loss of virulence. If transposable to humans, this would constitute a novel virus with a case fatality rate ~30 greater than that of Spanish flu.

A prevalent cancer susceptibility APOBEC3A hybrid allele bearing APOBEC3B 3'UTR enhances chromosomal DNA damage.

Human APOBEC3A (A3A) cytidine deaminase is a host enzyme that can introduce mutations into chromosomal DNA. As APOBEC3B (A3B) encodes a C-terminal catalytic domain ~91% identical to A3A, we examined its genotoxic potential as well as that of a highly prevalent chimaeric A3A-A3B deletion allele (ΔA3B), which is linked to a higher odds ratio of developing breast, ovarian and liver cancer. Interestingly, breast cancer genomes from ΔA3B(-/-) patients show a higher overall mutation burden.

The Irrationality of GOF Avian Influenza Virus Research.

The last two and a half years have witnessed a curious debate in virology characterized by a remarkable lack of discussion. It goes by the misleading epithet "gain of function" (GOF) influenza virus research, or simply GOF. As will be seen, there is nothing good to be gained.

Efficient deamination of 5-methylcytidine and 5-substituted cytidine residues in DNA by human APOBEC3A cytidine deaminase.

Deamination of 5-methylcytidine (5MeC) in DNA results in a G:T mismatch unlike cytidine (C) deamination which gives rise to a G:U pair. Deamination of C was generally considered to arise spontaneously. It is now clear that human APOBEC3A (A3A), a polynucleotide cytidine deaminase (PCD) with specificity for single stranded DNA, can extensively deaminate human nuclear DNA.