Few amino acid signatures distinguish HIV-1 subtype B pandemic and non-pandemic strains

Abstract

The Human Immunodeficiency Virus Type I (HIV-1) subtype B comprises approximately 10% of all HIV infections in the world. The HIV-1 subtype B epidemic comprehends a pandemic variant (named BPANDEMIC) disseminated worldwide and non-pandemic variants (named BCAR) that are mostly restricted to the Caribbean. The goal of this work was the identification of amino acid signatures (AAs) characteristic to the BCAR and BPANDEMIC variants. To this end, we analyzed HIV-1 subtype B full-length (n = 486) and partial (n = 814) genomic sequences from the Americas classified within the BCAR and BPANDEMIC clades and reconstructed the sequences of their most recent common ancestors (MRCA). Analysis of contemporary HIV-1 sequences revealed 13 AAs between BCAR and BPANDEMIC variants (four on Gag, three on Pol, three on Rev, and one in Vif, Vpu, and Tat) of which only two (one on Gag and one on Pol) were traced to the MRCA. All AAs correspond to polymorphic sites located outside essential functional proteins domains, except the AAs in Tat. The absence of stringent AAs inherited from their ancestors between modern BCAR and BPANDEMIC variants support that ecological factors, rather than viral determinants, were the main driving force behind the successful spread of the BPANDEMIC strain.

Fig 1. ML phylogenetic tree of 478 HIV-1 subtype B FL genome American sequences.

Branches are colored according to their classification in pandemic (B_PANDEMIC, n = 450) and non-pandemic (B_CAR; n = 28) lineages as indicated in the legend at the bottom right. Node support (SH-aLRT) for subtype B and B_PANDEMIC monophyletic groups are indicated. The tree was rooted using HIV-1 subtype D sequences. Branch lengths are drawn to scale with the bar at the bottom indicating nucleotide substitutions per site.

Fig 2. Mapping of the identified AAs between B_CAR and B_PANDEMIC on the accessory, regulatory and structural HIV-1 proteins.

For all proteins, their functional domains are represented; (A) Vif: regions responsible for the binding to APOBEC3G (A3G), APOBEC3F (A3F), Cullin 5 (Cul5), Elongin B (EloB), and Elongin C (EloC); (B) Vpu: the transmembrane domain, the cytoplasmic domain, and the linker region between them; (C) Tat: the N‐terminal acidic domain, the cysteine-rich domain, the hydrophobic core domain, the TAR binding domain, the glutamine-rich domain, and the RGD motif; (D) Rev: the RNA binding domain (RBD), that also functions as a nuclear localization signal (NLS), the nuclear exporting signal (NES), and sequences responsible for its multimerization (Mult.); (E) P24: the N-terminal domain and the C-terminal domain, connected by the inter-domain linker, the region mainly responsible for the interaction with cyclophilin A (CypA), and the major homology region (MHR); (F) Protease (PR): its active site.