Interactions of host APOBEC3 restriction factors with HIV-1 in vivo: implications for therapeutics

Abstract

Restriction factors are natural cellular proteins that defend individual cells from viral infection. These factors include the APOBEC3 family of DNA cytidine deaminases, which restrict the infectivity of HIV-1 by hypermutating viral cDNA and inhibiting reverse transcription and integration. HIV-1 thwarts this restriction activity through its accessory protein virion infectivity factor (Vif), which uses multiple mechanisms to prevent APOBEC3 proteins such as APOBEC3G and APOBEC3F from entering viral particles. Here, we review the basic biology of the interactions between human APOBEC3 proteins and HIV-1 Vif. We also summarize, for the first time, current clinical data on the in vivo effects of APOBEC3 proteins and survey strategies and progress toward developing therapeutics aimed at the APOBEC3-Vif axis.

Vif determines the requirement for CBF-β in APOBEC3 degradation

“…Several human APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3) proteins, notably APOBEC3D, APOBEC3F, APOBEC3G and APOBEC3H, have the capacity to restrict human immunodeficiency virus type 1 (HIV-1) replication (Albin & Harris, 2010;Desimmie et al, 2014;Feng et al, 2014;Kitamura et al, 2011;Refsland & Harris, 2013). These restriction factors are incorporated into the progeny virions and enzymically convert viral cDNA cytosines to uracils during reverse transcription, which can debilitate viral function (Albin & Harris, 2010;Desimmie et al, 2014;Feng et al, 2014;Kitamura et al, 2011;Refsland & Harris, 2013).…”

“…These restriction factors are incorporated into the progeny virions and enzymically convert viral cDNA cytosines to uracils during reverse transcription, which can debilitate viral function (Albin & Harris, 2010;Desimmie et al, 2014;Feng et al, 2014;Kitamura et al, 2011;Refsland & Harris, 2013). Although original studies focused on human APOBEC3G (Harris et al, 2003;Mariani et al, 2003;Sheehy et al, 2002;Zhang et al, 2003), subsequent work revealed that all placental mammals have APOBEC3 enzymes (Münk et al, 2012), albeit different numbers, and that these enzymes have the potential to attenuate the infectivity of a broad spectrum of viruses, including simian immunodeficiency virus (SIV) (Mariani et al, 2003), feline immunodeficiency virus (FIV) (Münk et al, 2008;Zielonka et al, 2010), bovine immunodeficiency virus (BIV) (LaRue et al, 2010) and small ruminant lentiviruses (SRLVs; e.g.…”

“…However, to counteract APOBEC3-mediated restriction, these lentiviruses encode a protein called Vif (viral infectivity factor). Vif recruits a cellular E3 ubiquitin ligase complex including cullin 5 (CUL5) and elongin B/C (ELOB/C), and degrades host APOBEC3 proteins through a ubiquitin/proteasomedependent pathway (Albin & Harris, 2010;Desimmie et al, 2014;Feng et al, 2014;Kitamura et al, 2011;Refsland & Harris, 2013).…”

IFN-α Induces APOBEC3G, F, and A in Immature Dendritic Cells and Limits HIV-1 Spread to CD4+ T Cells

“…The apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3 family (APOBEC3) proteins comprise six members of cytidine deaminases (6). The expression of APOBEC3G (A3G) is elevated in monocyte-derived DCs (MDDCs) upon maturation, leading to suppression of reverse transcription and introduction of G-to-A hypermutations in the viral genome.…”

“…The expression of APOBEC3G (A3G) is elevated in monocyte-derived DCs (MDDCs) upon maturation, leading to suppression of reverse transcription and introduction of G-to-A hypermutations in the viral genome. Two other members of the A3 family, A3F and A3A, were also shown to be expressed in MDDCs and exert antiviral activity (6)(7)(8). Although humans have evolved powerful retroviral restriction factors, HIV-1 has acquired specific means to antagonize these antiviral defense mechanisms.…”