APOBEC3 Cytidine Deaminases: Distinct Antiviral Actions along the Retroviral Life Cycle

Abstract

The field of human immunodeficiency virus (HIV) biology has been galvanized by the discovery of innate APOBEC3 cytidine deaminases, which pose powerful barriers to the replication of HIV and other retroviruses. Rapid progress has been made in defining their action, intriguing regulation within cells, expanded range of retroviral targets, and counterstrikes utilized by retroviruses against them. Although scientifically fascinating, advances in APOBEC3 biology may lead to new antiviral drugs and improved lentiviral vectors for gene therapy.

Stimulation of Cell Surface CCR5 and CD40 Molecules by Their Ligands or by HSP70 Up-Regulates APOBEC3G Expression in CD4+ T Cells and Dendritic Cells

“…This interaction has raised therapeutic potentials, by either inhibiting Vif activity or boosting A3G levels above the neutralizing capacity of Vif to inhibit virus replication (5,26). The present studies have been confined to exploring the potential of up-regulating A3G expression first in vitro and then in vivo.…”

Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

“…A3G expression is enhanced in T cells by interleukin-2 (IL-2), IL-15, and, to a lesser extent, IL-7, as well as in DCs after exposure to a combination of tumor necrosis factor alpha (TNF-␣) and poly(I:C) (62). A3G is an innate barrier affording broad intracellular antiretroviral protection (15,16,58). The characterization of A3G has been carried out in T cells (17) or with recombinant A3G purified from insect cells (12), showing that the low-molecular-mass (LMM) complexes of A3G contain the antiretroviral activity.…”

APOBEC3G and HIV-1: Strike and counterstrike

“…In the absence of Vif, A3G is recruited into budding virions through its interaction with the nucleocapsid component of the Gag polyprotein and/or HIV genomic RNA, as depicted in Figure 1A (number 1) and reviewed elsewhere [9][10][11]. These viruses are consequently rendered noninfectious because virion-encapsidated A3G undermines an integral subsequent step in the viral life cycle: reverse transcription.…”

“…During reverse transcription, the RNA genome is first converted into a minus single-stranded DNA (ssDNA), which in turn serves as the template for the synthesis of a complementary plus (coding) strand to form a doublestranded DNA copy of the RNA genome. It is the minus ssDNA that A3G targets for deamination, converting deoxycytidines (dC) to deoxyuridines (dU) primarily at dCdC sites [9][10][11], with the frequency of mutation influenced by the duration of single strandedness [12••]. Although not fully understood, the presence of these dU residues may initiate nontemplate DNA repair by uracil DNA glycosylase [13] in an attempt to eliminate the unwanted uracil residues.…”