Modulation of dendritic cell immune responses by Envelope, and not functional fitness, might be important for subtype C HIV-1 transmission
Evelyn Ngwa Lumngwena1,2, Bahiah Meyer3, Riley Traviss3 and Zenda Woodman3
1Institute for Medical Research and Medicinal Plants Research, MINRESI, Cameroon; 2Faculty of Health Sciences, University of Cape Town, South Africa
HIV-1 Envelope (Env) plays a major role in the competitive ability of the virus and a number of studies have investigated the role that it might play in transmission. One such study identified subtype B transmission motifs: a Histidine at position 12 (H12) of the signal peptide and the absence of a potential N-glycosylation site (PNG) at position 413 (N413), suggested to enhance viral fitness and/or facilitate escape from immune responses. We determined how Env might contribute to the selective advantage of subtype C transmitted founders (TF) by: 1) comparing four TF Env to matched chronic infection (CI) variants, and 2) characterising the impact of H12 and N413 on Env processing and phenotype. All nine subtype C Envs carried a Glutamic acid at position 12 (Q12) and a PNG at 413 representative of the population frequency, suggesting that subtype B TFs might have evolved by a pathway distinct from other subtypes. When a subtype C TF Env was mutated, pseudovirus (PSV) infectivity of constructs Q12H and Q12A decreased significantly, suggesting that H12 was not linked to enhanced infectivity as reported for subtype B TF. On the contrary, deletion of N413 significantly increased PSV entry efficiency, suggesting that even though the presence of a PNG at this site had a fitness cost, it was conserved in subtype C variants, including TFs. Furthermore, the processing and phenotype of TF Envs and PSV entry efficiency did not differ significantly from matched CI variants supporting the suggestion that Env functional fitness was not important for subtype C transmission. However, TFs were better able to stimulate monocyte derived dendritic cells (MDDCs) to secrete higher levels of IL-10, TNF-α, IL-6, IL-8 and MIP1β than their matched CI counterparts. This suggests that subtype C TFs might have the ability to induce immune responses in the female genital tract that favour transmission. Overall, HIV-1 subtype C transmission might not be dependent on Env function but rely more on its ability to induce dendritic cell-mediated immune responses that promote HIV survival within the female genital tract.