The role of HIV-1 subtype B Envelope transmission motifs in subtype C variant infectivity
Master Thesis
2018
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University of Cape Town
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Abstract
Transmitted founders (TF) might carry motifs that provide a phenotypic advantage that enables human immunodeficiency virus type-1 (HIV-1) to overcome immune barriers within the female genital tract. One study compared over 5000 subtype B TF and mismatched chronic infection envelope (env) sequences and identified two putative transmission motifs: Histidine at position 12 of the signal peptide (His12) and a potential N-glycan site (PNG) at position 413-415. Although, His12 was shown to be important for subtype B Env expression and viral infectivity, in our own sequence analysis subtype C variants did not carry the transmission motifs and the aim of this study was to determine whether His12 and PNG413 was important for subtype C Env expression, processing, function and viral replication. Mutagenesis of a subtype C Env clone indicated that His12 decreased pseudovirion (PSV) entry efficiency without influencing Env expression, secretion and cleavage with no changes in the N-glycosylation profile. This suggested that His12 had a fitness cost and was thus selected against. However, His12 significantly enhanced the entry efficiency of infectious molecular clones (IMCs), suggesting that it might be beneficial for in vivo replication. The variation between the PSV and IMC entry of TZM-bl cells could be due to differences in assay conditions. On the other hand deletion of PNG413 enhanced Env expression, secretion, cleavage and PSV and IMC entry efficiency of TZM-bl cells. This would suggest that subtype C TFs carrying a PNG at 413-413 would have lower viral replicative capacity due to poor expression and processing of Env. The benefit of this phenotype on HIV-1 subtype C transmission needs to be further investigated. Unfortunately, PSV and IMC entry of TZM-bl cells could not be confirmed by IMC replication in peripheral blood monocytes because the clones could not replicate to measurable levels in these cells over the culture period. Overall, this study has shown that amino acid residues at positions 12 and 415 do play a role in modulating Env processing and function however the actual mechanism by which these polymorphisms impact viral fitness most likely differ to that of subtype B, explaining why His12 is absent and PNG413 is present in subtype C TFs.
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Meyer, B. 2018. The role of HIV-1 subtype B Envelope transmission motifs in subtype C variant infectivity. University of Cape Town.