PubMed · 15937460
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Apoorva Mandavilli. 2005. Profile: Michael Malim.. https://doi.org/10.1038/nm0605-586
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APOBEC3G is an antiviral host factor capable of inhibiting the replication of both exogenous and endogenous retroviruses as well as hepatitis B, a DNA virus that replicates through an RNA intermediate. To gain insight into the mechanism whereby APOBEC3G restricts retroviral replication, we investigated the subcellular localization of the protein. Herein, we report that APOBEC3G localizes to mRNA processing (P) bodies, cytoplasmic compartments involved in the degradation and storage of nontranslating mRNAs. Biochemical analysis revealed that APOBEC3G localizes to a ribonucleoprotein complex with other P-body proteins which have established roles in cap-dependent translation (eIF4E and eIF4E-T), translation suppression (RCK/p54), RNA interference-mediated post-transcriptional gene silencing (AGO2), and decapping of mRNA (DCP2). Similar analysis with other APOBEC3 family members revealed a potential link between the localization of APOBEC3G and APOBEC3F to a common ribonucleoprotein complex and P-bodies with potent anti-HIV-1 activity. In addition, we present evidence suggesting that an important role for HIV-1 Vif, which subverts both APOBEC3G and APOBEC3F antiviral function by inducing their degradation, could be to selectively remove these proteins from and/or restrict their localization to P-bodies. Taken together, the results of this study reveal a novel link between innate immunity against retroviruses and P-bodies suggesting that APOBEC3G and APOBEC3F could function in the context of P-bodies to restrict HIV-1 replication.
To defend against external pathogens, metazoan organisms have evolved numerous defenses that generally fall within the innate and adaptive immune responses. Considerable effort continues to focus on developing a vaccine to manipulate the adaptive immune system to protect against or control HIV-1. However, recent advances in our understanding of the innate immune system have revealed that cells have a potent intrinsic antiretroviral defense in the form of APOBEC3G, which is a member of a larger family of cytidine deaminases that are active against HIV-1 and other retroviruses. Insights into how the action of A3G is circumvented by HIV-1 through the action of its Vif protein, and the surprising mechanisms by which A3G is regulated within the cell, offer exciting new opportunities for developing novel anti-HIV-1 therapies that exploit this intrinsic antiretroviral system.
Reverse transcription (RTn) in HIV-infected cells occurs in a nucleoprotein complex termed the reverse transcription complex (RTC). RTCs containing RT activity and integrase (IN) were shown to be heterogeneous in size and density on sucrose velocity and equilibrium gradients. WT and Vif-deficient (Deltavif) RTCs produced by infection with virus from permissive cells displayed similar sedimentation characteristics, while RTCs from Deltavif virus produced in non-permissive cells demonstrated a reduction in the major RTC form and more of the RTn products in rapidly sedimenting structures. APOBEC3G derived from virions did not co-sediment with RTCs, but RTCs from Deltavif infections showed elevated levels of mutations in RTn products, consistent with APOBEC3G and other mutational mechanisms. The most mutated transcripts were present within rapidly sedimenting RTCs. Thus, virus without functional vif, produced from non-permissive cells, forms abnormal RTCs that contain increased mutation of RTC-associated RTn products in newly infected target cells.