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.
HIV-1 group M was transmitted to humans nearly one century ago. The virus has since diversified to form distinct clades, which spread to multiple regions worldwide. Of the different proteins encoded by HIV-1, the envelope glycoproteins (Envs) have diversified most rapidly in all infected populations. We compared the range of variants that emerged during the AIDS pandemic in diverse HIV-1 clades and distinct geographic regions. Our analyses focused on two components of Env that contain multiple epitopes of broadly-neutralizing antibodies: the glycan shield and apex domain. Interestingly, at each Env position, the amino acid in the inferred clade ancestor was replaced by a unique combination of emerging variants. Key antigenic sites and genetic signatures of vaccine protection have gradually evolved toward conserved frequency distributions (FDs) of all amino acids. FDs are specific for position and clade and are highly conserved in populations from different regions. Remarkably, founder effects of Env mutations in distinct clades and recently-infected regions were significantly reduced during the epidemic by evolution of each site toward the position-specific FD.These findings suggest that the selective pressures that guide evolution of Env are conserved in different populations. They are sufficiently strong to reduce founder effects at the clade and regional levels and have significantly altered the distribution of Env forms that circulate worldwide. Consequently, the intra-population diversity of the Env protein continues to increase whereas the inter-population diversity is gradually decreasing. 35 36 2 Importance 37The Env protein of HIV-1 is the primary target in AIDS vaccine design. Due to frequent 38 mutations, new Env variants continuously emerge in the population. The increasing number of 39Env forms and apparent randomness of the changes limit our ability to design broadly-effective 40 vaccines. We examined the populations-level changes that occurred in Env during the AIDS 41 epidemic. Each position of the molecule has evolved toward a specific combination of amino 42 acids. Similar changes occurred in different HIV-1 subtypes and geographic regions toward the 43 same sets of forms, often from distinct ancestral sequences. Such conserved patterns of 44 evolution define a new framework for designing vaccines that are tailored to the unique 45 combination of Env variants expected to circulate in each population. 46 47The founder virus of HIV-1 group M was transmitted to humans in the early part of the 49 20 th century (1-3). Due to low fidelity of the viral replication machinery, frequent mutations are 50 introduced in the HIV-1 genome (1, 2). The group M founder thus gradually diversified to create 51 different genetic lineages (clades), which spread to multiple regions of the world (3, 4). In some 52 regions, a single founder was introduced that accounts for most circulating strains, such as the 53 clade B lineage in Korea (5) or the clade C lineage in India (6, 7). In other regions, multiple 54founder l...
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