APOBEC3G/F as one possible driving force for co-receptor switch of the human immunodeficiency virus-1

Abstract

Human immunodeficiency virus-1 tropism highly correlates with the amino acid (aa) composition of the third hypervariable region (V3) of gp120. A shift towards more positively charged aa is seen when binding to CXCR4 compared with CCR5 (X4 vs. R5 strains), especially positions 11 and 25 (11/25-rule) predicting X4 viruses in the presence of positively charged residues. At nucleotide levels, negatively or uncharged aa, e.g., aspartic and glutamic acid and glycine, which are encoded by the triplets GAN (guanine-adenosine-any nucleotide) or GGN are found more often in R5 strains. Positively charged aa such as arginine and lysine encoded by AAR or AGR (CGN) (R means A or G) are seen more frequently in X4 strains suggesting our hypothesis that a switch from R5 to X4 strains occurs via a G-to-A mutation. 1527 V3 sequences from three independent data sets of X4 and R5 strains were analysed with respect to their triplet composition. A higher number of G-containing triplets was found in R5 viruses, whereas X4 strains displayed a higher content of A-comprising triplets. These findings also support our hypothesis that G-to-A mutations are leading to the co-receptor switch from R5 to X4 strains. Causative agents for G-to-A mutations are the deaminases APOBEC3F and APOBEC3G. We therefore hypothesize that these proteins are one driving force facilitating the appearance of X4 variants. G-to-A mutations can lead to a switch from negatively to positively charged aa and a respective alteration of the net charge of gp120 resulting in a change of co-receptor usage.

Incomplete APOBEC3G/F Neutralization by HIV-1 Vif Mutants Facilitates the Genetic Evolution from CCR5 to CXCR4 Usage

“…Our study suggests that the APOBEC3G-driven mutagenesis can also play a role in this phenomenon. This hypothesis is also consistent with recent in vivo and in vitro studies (3,31). By analyzing 26 longitudinal samples from 10 patients, Heger et al described an in vivo increase of G-to-A mutations (all occurring in a GG or GA dinucleotide context) coding for substitutions at positions 22, 24, and 25, which are associated with CXCR4 usage (3).…”

“…Several members of the APOBEC3 family (A to H) show different degrees of antiviral potency, with APOBEC3G and APOBEC3F generally regarded as exerting the strongest HIV-1 restriction in peripheral blood mononuclear cells (PBMC) and in monocyte-derived-macrophages (MDM), respectively (2)(3)(4)(5).…”

“…1) (27)(28)(29)(30)(31)(32)(33)(34)(35). Recent studies supposed a role of APOBEC3 proteins in inducing G-to-A nucleotide mutations in the V3 region (3,31). However, those studies were limited to in silico observations or to investigation of members of the APOBEC3 family other than APOBEC3G/F (such as APOBEC3D).…”

The Road Less Traveled: HIV's Use of Alternative Routes through Cellular Pathways

“…APOBEC3 proteins are cytidine deaminases and act as antiviral agents by lethally introducing C-to-U mutations and being targeted by the HIV-1 Vif protein for proteasomal degradation (reviewed in reference 58). Such a mechanism might be a driver in the HIV-1 CCR5/CXCR4 coreceptor switch during the course and progression of disease consistent with a G-to-A mutational signature of APOBEC3s (63). A recent study examining the footprints of APOBECs from chronically infected patients found that, whereas APOBEC3G-induced mutagenesis is lethal to HIV-1, mutagenesis caused by APOBEC3F and/or other deaminases may result in sublethal mutations that might facilitate viral diversification (64).…”

Vaccination against infectious diseases: What is promising?

“…Albeit biggest labour no efficacious vaccination could be produced up to date [5]. However, pathogenic research is in progress looking for measures to enhance the cellular-mediated immune response [66][67][68][69][70][71].…”