Dissecting the Dynamics of HIV-1 Protein Sequence Diversity

Abstract

The rapid mutation of human immunodeficiency virus-type 1 (HIV-1) and the limited characterization of the composition and incidence of the variant population are major obstacles to the development of an effective HIV-1 vaccine. This issue was addressed by a comprehensive analysis of over 58,000 clade B HIV-1 protein sequences reported over at least 26 years. The sequences were aligned and the 2,874 overlapping nonamer amino acid positions of the viral proteome, each a possible core binding domain for human leukocyte antigen molecules and T-cell receptors, were quantitatively analyzed for four patterns of sequence motifs: (1) “index”, the most prevalent sequence; (2) “major” variant, the most common variant sequence; (3) “minor” variants, multiple different sequences, each with an incidence less than that of the major variant; and (4) “unique” variants, each observed only once in the alignment. The collective incidence of the major, minor, and unique variants at each nonamer position represented the total variant population for the position. Positions with more than 50% total variants contained correspondingly reduced incidences of index and major variant sequences and increased minor and unique variants. Highly diverse positions, with 80 to 98% variant nonamer sequences, were present in each protein, including 5% of Gag, and 27% of Env and Nef, each. The multitude of different variant nonamer sequences (i.e. nonatypes; up to 68%) at the highly diverse positions, represented by the major, multiple minor, and multiple unique variants likely supported variants function both in immune escape and as altered peptide ligands with deleterious T-cell responses. The patterns of mutational change were consistent with the sequences of individual HXB2 and C1P viruses and can be considered applicable to all HIV-1 viruses. This characterization of HIV-1 protein mutation provides a foundation for the design of peptide-based vaccines and therapeutics.

Cell‐mediated anti‐Gag immunity in pharmacologically induced functional cure of simian AIDS: a ‘bottleneck effect’?

“…The high mutation rate and consequent variability of retroviruses is one of the key obstacles to the development of effective vaccines and curative interventions for HIV infection. To circumvent this problem, several investigators have attempted to identify, and exploit, regions of the HIV proteome that are conserved in different viral strains [2, 44,72]. Our results support the concept that the efficacy of cell-mediated immunity may depend on its targeting of sequences with low-level variability.…”

CA Mutation N57A Has Distinct Strain-Specific HIV-1 Capsid Uncoating and Infectivity Phenotypes

“…Indeed, an analysis of over 40,000 Gag sequences from primary isolates of multiple subtypes demonstrated the polymorphic nature of all four of these CA positions, including the residues present in HIV-1 NL4-3 and HIV-1 LAI . Within subtype B, Gag (including CA) shows low overall sequence diversity (66), and across all subtypes the N-terminal region of CA, along with IN, contains the lowest levels of amino acid diversity within the HIV-1 genome (67). The frequency of HIV-1 NL4-3 and HIV-1 LAI amino acids across all CA positions showed strong conservation, with over 90% of CA sequences matching HIV-1 NL4-3 and HIV-1 LAI at the vast majority of the positions.…”

Vaccine Target Discovery

“…The output alignment quality will be manually inspected for any errors and/or misalignments, which are common when dealing with partial sequences. Henceforth, the data would be ready for analyses, which can involve performing a diversity analysis, such as by measuring entropy values (Heiny et al, 2007;Hu et al, 2013;Khan et al, 2008;Koo et al, 2009) and quantifying variant motifs for each, user-defined, k-mer positions in the alignment. The results of these analyses will be plotted as an output for the user, providing a holistic view of the diversity, including variant distribution.…”

“…Reverse vaccinology immunoinformatics approaches are widely applied for viral vaccine design, such as for influenza virus, chikungunya virus, zika virus and others (Gupta et al, 2016;María et al, 2017), including parasites (Damfo et al, 2017) and bacteria Zahroh et al, 2016;Rappuoli, 2001). Khan et al developed a bioinformatics pipeline for DENV, which proved generic as it was successfully applied to several viruses, such as WNV (Koo et al, 2009), a close relative of DENV (Khan et al, 2008), and a number of other viruses, such as HIV-1 (Hu et al, 2013), among others. It provides a novel and generalized approach to the formulation of peptide-based vaccines targeting a broad diversity of pathogens and applicable to the human population at large.…”

“…This approach therefore significantly reduces the efforts and cost of experimentation, while providing for systematic screening and analyses of pathogen proteomes (Raman et al, 2014). Khan et al (2008), Koo et al (2009) and Hu et al (2013) analyzed a large number of dengue (DENV), West Nile virus (WNV) and clade B HIV-1, sequences, respectively, retrieved from the NCBI Entrez protein database ( Table 1). The sequences were aligned and the overlapping nonamer amino acid positions of the viral proteome, each a possible core binding domain for human leukocyte antigen molecules and T-cell receptors, were quantitatively analyzed.…”