Abstract
Human immunodeficiency virus (HIV) is subject to immune selective pressure soon after it establishes infection at the founder stage. As an individual progresses from the founder to chronic stage of infection, immune pressure forces a history of mutations that are embedded in envelope sequences. Determining this pathway of coevolving mutations can assist in understanding what is different with the founder virus and the essential pathways it takes to maintain infection. We have combined operations research and bioinformatics methods to extract key networks of mutations that differentiate founder and chronic stages for 156 subtype B and 107 subtype C envelope (gp160) sequences. The chronic networks for both subtypes revealed strikingly different hub-and-spoke topologies compared to the less structured transmission networks. This suggests that the hub nodes are impacted by the immune response and the resulting loss of fitness is compensated by mutations at the spoke positions. The major hubs in the chronic C network occur at positions 12, 137 (within the N136 glycan), and 822, and at position 306 for subtype B. While both founder networks had a more heterogeneous connected network structure, interestingly founder B subnetworks around positions 640 and 837 preferentially contained CD4 and coreceptor binding domains. Finally, we observed a differential effect of glycosylation between founder and chronic subtype B where the latter had mutational pathways significantly driven by N-glycosylation. Our study provides insights into the mutational pathways HIV takes to evade the immune response, and presents features more likely to establish founder infection, valuable for effective vaccine design.
Highlights
After establishing Human immunodeficiency virus (HIV) infection, the founder virus, which is typically monoclonal, comes under increasing immune pressure—especially from the humoral response to p24, gp41 and gp120 [1]
The inferred monoclonal transmission HIV Env sequences had been determined for 78 subtype B and 55 subtype C cases [7,8], and as previously described [9], a similar number of chronic Env sequences were obtained from the Los Alamos National Laboratory (LANL) HIV sequence database, frequency-matched to the geographical regions of the founder sequences
Regardless of HIV subtype, the chronic networks contained high-degree hubs where the connecting spokes expressed a consistent residue at the hub
Summary
After establishing HIV infection, the founder virus, which is typically monoclonal, comes under increasing immune pressure—especially from the humoral response to p24, gp and gp120 [1]. It is likely that many mutations either fail to sufficiently change its recognition by the immune response, or lead to envelope spikes that are incapable of infection. The virus must continue to evolve along the successful mutational pathways as immune pressure evolves. These stepwise functional changes in the HIV envelope (Env) glycoprotein gp160 (gp120/gp41) should appear as covarying amino acid (AA) mutations embedded in Env sequences. A vaccine that engenders sufficiently early blocks to these pathways may hinder evolution of the founder virus and result in HIV clearance before it is established
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