Restriction of vif-competent HIV-1 by physiological levels of APOBEC3G in primary T-helper cells

Abstract

Apolipoprotein B mRNA-editing complex 3G and 3F (APOBEC3G, A3G, A3F) reduce endogenous retrotransposition and also limit the replication of HIV-1. These cytidine deaminases have anti-HIV activity when packaged into virions, if not antagonized by the HIV-1 protein vif, and also when present in an endogenous target cell’s cytoplasm. The aim of this study was to gain an understanding of how expression of A3G is regulated in primary cells and if physiological levels of expression of A3G could overcome the vif counter measure of HIV-1. These studies demonstrate that differentiation from naïve T cells to specific CD4+ T helper subtypes regulates the expression of A3G; with increases in T helper type 1 (Th1) subtype cells and relative decreases in T helper type 2 (Th2) subtype cells. Within the Th1 subtype cells, sufficient A3G is expressed to overcome vif in the producer cell. This allows for packaging of A3G in virions, reducing infectivity of Th1 cell-produced virions relative to virions produced from Th2 cells. These studies also reveal that Th1 cells maintain a greater cytoplasmic A3G-dependent restriction to incoming wild-type HIV-1 infection than do Th2 cells. These data support the conclusion that A3G expression in primary T helper cells is capable of partially restricting vif-positive HIV-1 by both its virion-packaged and target cell activities and suggest strategies for novel therapies.