A single amino acid difference in the host APOBEC3G protein controls the primate species specificity of HIV type 1 virion infectivity factor

Abstract

The HIV type 1 (HIV-1) virion infectivity factor (Vif) protein blocks the action of the host defense factor APOBEC3G in human cells, thereby allowing release of infectious virions, but fails to inhibit similar APOBEC3G proteins present in some simian cells. Conversely, the Vif protein encoded by the African green monkey (agm) simian immunodeficiency virus (SIV) can block agm APOBEC3G function but fails to inhibit human APOBEC3G. This difference plays a key role in determining the primate species tropism of HIV-1 and SIV agm. Here, we demonstrate that a single APOBEC3G residue, which is an aspartic acid in human APOBEC3G and a lysine in agm APOBEC3G, controls the ability of the HIV-1 Vif protein to bind and inactivate these host defense factors. These data identify a critical charged residue that plays a key role in mediating the formation of the distinct Vif:APOBEC3G complexes formed in human and simian cells. Moreover, these results suggest that the biological barrier preventing the entry of additional SIV into the human population as zoonotic infections is potentially quite fragile.

HIV-1 Vif-mediated ubiquitination/degradation of APOBEC3G involves four critical lysine residues in its C-terminal domain

“…Abrogation of Vif binding by A3G could also confer resistance to Vif-dependent degradation, as was observed for the D128K mutant (27)(28)(29)(30). It therefore seemed prudent to determine whether Arg substitutions at A3G residues 297, 301, 303, and 334 would in any way interfere with A3G's ability to bind Vif.…”

“…The region in A3G responsible for binding to HIV-1 Vif was initially identified by comparative studies of the species specificity of A3G degradation by Vif. Thus, a single amino acid difference in hA3G, Asp at position 128 versus Lys in the A3G of African green monkeys (A3G agm ), determines species specificity by influencing Vif-A3G binding (27)(28)(29)(30). Furthermore, extensive site-directed mutagenesis revealed that the 128 DPD 130 motif of A3G, located near the first Zn cluster, is crucial for direct binding to HIV-1 Vif.…”

Inhibition of HIV-1 replication by simian restriction factors, TRIM5α and APOBEC3G

“…Recent studies demonstrated that single aminoacid substitutions in the human TRIM5a and human APOBEC3G could render the human proteins potent restriction factors against HIV-1. [33][34][35][36][37] Thus, as suggested by Yap et al, 37 we can use the R332P derivative of human TRIM5a, in combination with the Vif-insensitive, K128D derivative of human APOBEC3G, as ideal alternatives to reduce host immune response to the restriction factors.…”

Identification of a Novel HIV-1 Inhibitor Targeting Vif-dependent Degradation of Human APOBEC3G Protein

“…This species specificity was demonstrated by altering a single amino acid in the Vifbinding site, 128 DPD 130 of huA3G. The D128K mutation controls species specificity (34,35,37,38 (40, 41, 46 -49). Small molecules that inhibit HIV-1 Vif function in vitro have recently been identified, but these compounds do not inhibit the Vif-A3G interaction (50 -53).…”