Differential Requirement for Conserved Tryptophans in Human Immunodeficiency Virus Type 1 Vif for the Selective Suppression of APOBEC3G and APOBEC3F

Abstract

APOBEC3G (A3G) and related cytidine deaminases, such as APOBEC3F (A3F), are potent inhibitors of retroviruses. Formation of infectious human immunodeficiency virus type 1 (HIV-1) requires suppression of multiple cytidine deaminases by Vif. Whether HIV-1 Vif recognizes various APOBEC3 proteins through a common mechanism is unclear. The domains in Vif that mediate APOBEC3 recognitions are also poorly defined. The N-terminal region of HIV-1 Vif is unusually rich in Trp residues, which are highly conserved. In the present study, we examined the role of these Trp residues in the suppression of APOBEC3 proteins by HIV-1 Vif. We found that most of the highly conserved Trp residues were required for efficient suppression of both A3G and A3F, but some of these residues were selectively required for the suppression of A3F but not A3G. Mutant Vif molecules in which Ala was substituted for Trp79 and, to a lesser extent, for Trp11 remained competent for A3G interaction and its suppression; however, they were defective for A3F interaction and therefore could not efficiently suppress the antiviral activity of A3F. Interestingly, while the HIV-1 Vif-mediated degradation of A3G was not affected by the different C-terminal tag peptides, that of A3F was significantly influenced by its C-terminal tags. These data indicate that the mechanisms by which HIV-1 Vif recognizes its target molecules, A3G and A3F, are not identical. The fact that several highly conserved residues in Vif are required for the suppression of A3F but not that of A3G suggests a critical role for A3F in the restriction of HIV-1 in vivo.APOBEC3G (A3G) and the related cytidine deaminase APOBEC3F (A3F) are potent inhibitors of a wide range of retroviruses and retroelements (2,

Cytidine deamination induced HIV-1 drug resistance

“…Most of our understanding about APOBEC3 activity and corresponding Vif defects has been gained by using overexpression systems (18,19,25). In this study, we demonstrate that HIV-1 Vif mutants with suboptimal anti-APOBEC3G activity display reduced fitness in a multiple round replication assay with human PBMCs.…”

“…Protection of HIV-1 from cytidine deamination in vivo, however, is not absolute, because full-length Vif alleles that fail to neutralize one or several APOBEC3 enzymes have been identified (18,19). Indeed, HIV-1 sequences carrying the genetic footprints of past deamination have been detected in treated and untreated chronically infected patients (20)(21)(22), vertically infected infants (23), and long-term nonprogressors (18,24) suggesting that variations in HIV-1 Vif's anti-APOBEC3 activity occur in many different clinical settings.…”

HIV-1 and HIV-2 Vif Interact with Human APOBEC3 Proteins Using Completely Different Determinants

“…In addition, we identified a region important for A3H-hapII neutralization that is not required for A3F or A3G neutralization. Studies conducted by us and others have determined that Vif1 also has distinct regions for the neutralization of A3F, A3G, and A3H-hapII (34)(35)(36)(37)(38)(39). It is important to point out that it cannot be concluded that these motifs that have been identified to be critical for interaction through mutational analyses are themselves directly involved in the protein-protein interactions.…”

“…Vif1 interacts with numerous host cell proteins to form a ubiquitin ligase complex consisting of cullin 5, elongin B, and elongin C (29), RING finger protein 2 (30,31), and CBF␤ (32,33). Further, Vif1 has several domains through which it binds APOBEC3 proteins, with some regions being specific for certain APOBEC3s (34)(35)(36)(37)(38)(39). For example, the 40 YRHHY 44 motif of Vif1 is known to play a critical role in inducing the degradation of A3G, while the 14 DRMR 17 region is known to be critical for inducing the degradation of A3C, A3D, and A3F (34).…”

APOBEC proteins and intrinsic resistance to HIV-1 infection

“…These shared features of A3G and A3F seemingly accord with the view that these are the most significant APOBEC enzymes in terms of natural HIV-1 infection (namely in humans). Interestingly, the sequence elements within HIV-1 Vif required for inhibition of A3G versus A3F differ from each other (Simon et al 2005;Tian et al 2006;Russell & Pathak 2007), implying that evolutionary pressures have selected for the ability to suppress both proteins. Moreover, A3G and A3F are both expressed in human CD4 T cells (the principal target for HIV-1 infection in vivo), further supporting the notion that both enzymes naturally encounter HIV-1, and that the virus must have evolved to evade the anti-viral activities of each of them.…”