Key Positions of HIV-1 Env and Signatures of Vaccine Efficacy Show Gradual Reduction of Population Founder Effects at the Clade and Regional Levels

Abstract

HIV-1 group M was transmitted to humans nearly one century ago. The virus has since evolved to form distinct clades, which spread to different regions of the world. The envelope glycoproteins (Envs) of HIV-1 have rapidly diversified in all infected populations. We examined whether key antigenic sites of Env and signatures of vaccine efficacy are evolving toward similar or distinct structural forms in different populations worldwide. Patterns of amino acid variants that emerged at each position of Env were compared between diverse HIV-1 clades and isolates from different geographic regions. Interestingly, at each Env position, the amino acid in the clade ancestral or regional-founder virus was replaced by a unique frequency distribution (FD) of amino acids. FDs are highly conserved in populations from different regions worldwide and in paraphyletic and monophyletic subclade groups. Remarkably, founder effects of Env mutations at the clade and regional levels have gradually decreased during the pandemic by evolution of each site toward the unique combination of variants. Therefore, HIV-1 Env is evolving at a population level toward well-defined “target” states; these states are not specific amino acids but rather specific distributions of amino acid frequencies. Our findings reveal the powerful nature of the forces that guide evolution of Env and their conservation across different populations. Such forces have caused a gradual decrease in the interpopulation diversity of Env despite an increasing intrapopulation diversity. IMPORTANCE The Env protein of HIV-1 is the primary target in AIDS vaccine design. Frequent mutations in the virus increase the number of Env forms in each population, limiting the efficacy of AIDS vaccines. Comparison of newly emerging forms in different populations showed that each position of Env is evolving toward a specific combination of amino acids. Similar changes are occurring in different HIV-1 subtypes and geographic regions toward the same position-specific combinations of amino acids, often from distinct ancestral sequences. The predictable nature of HIV-1 Env evolution, as shown here, provides a new framework for designing vaccines that are tailored to the unique combination of variants expected to emerge in each virus subtype and geographic region.

Geospatial HIV-1 subtype C gp120 sequence diversity and its predicted impact on broadly neutralizing antibody sensitivity

“…Kumar et al 2018a). The trimeric Env glycoproteins on the virus surface are the most diverse of all proteins encoded by HIV-1; which differs by greater than 20% of amino acids between matched subtype (Gnanakaran et al 2007; Han et al 2020; Hraber et al 2014; Korber et al 2001; Lynch et al 2009) and which continues to diversify at a population level (Bouvin-Pley et al 2013; Bunnik et al 2010; DeLeon et al 2017; Hraber et al 2014). This has been substantiated by observation that several epitopes that are targeted by different bnAbs those have been found to vary over time (DeLeon et al 2017).…”

The fusion peptide proximal region of the HIV-1 envelope glycoproteins regulates exposure of immunogenic epitopes at the trimer base

“…In different populations worldwide infected by virus from the same HIV-1 clade, each Env position exhibits a similar frequency distribution of amino acids (13). In many cases, founder effects of substitutions in monophyletic lineages are reduced by evolution of the position toward the clade-specific frequency distribution.…”

“…They observed that in distinct geographic regions, each Env position has evolved toward a specific frequency distribution of amino acids that replaced the regional ancestral form. The frequency distribution is specific for HIV-1 clade and is similar in monophyletic and paraphyletic lineages, suggesting that, at a population level, Env encounters similar selective pressures (13).…”

“…were not included due to lack of substantial diversity. Clade B Envs isolated from samples collected worldwide between and 2016 were analyzed (13). For consecutive 5-7-year periods, we calculated at each position the frequency of emerging variants (i.e., non-ancestral residues).…”

“…In a recent study by Han et al, the authors analyzed the population-level distribution of amino acids at different positions of Env (13). They observed that in distinct geographic regions, each Env position has evolved toward a specific frequency distribution of amino acids that replaced the regional ancestral form.…”