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Deep sequence analysis of HIV adaptation following vertical transmission: Importance of human leucocyte antigen-driven selection on the evolution of HIV

Gaudieri, S., Currenti, J., John, M., McKinnon, E., Leary, S., Chopra, A., Pilkington, M., Smith, R., Barnett, L., McDonnell, W., Lucas, M., Mallal, S., Conrad, J. and Kalams, S. (2019) Deep sequence analysis of HIV adaptation following vertical transmission: Importance of human leucocyte antigen-driven selection on the evolution of HIV. Journal of the International AIDS Society, 22 (S5). p. 39.

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Background: HIV can adapt to an individual's T cell immune response via mutations that affect antigen recognition and disease outcome. These viral adaptations are specific to the host's human leucocyte antigen (HLA) alleles, as these molecules determine which peptides are presented to T cells. Transmitted viral adaptations can be maintained or undergo reversion in a new host dependent on the cost‐benefit balance. We used the unique features of vertical HIV transmissions, primarily a known source of transmitted virus and sharing of HLA alleles that restrict T cell epitope specificity, to predict the in vivo replicative capacity and immune escape benefit of specific HIV adaptations that could be used to inform vaccine design.

Methods: A deep sequencing approach was utilised to determine the HIV clade B quasispecies in 26 confirmed mother‐to‐child transmission pairs where the potential for founder viruses to be pre‐adapted is high due to the pairs being haplo‐identical at HLA loci. This scenario allowed the assessment of the dynamics of known HIV adaptations following transmission in either a non‐selective environment (mediated by HLA mismatched to original selecting HLA), or selective immune environment (mediated by shared HLA alleles). Anti‐HIV‐specific IFN‐ϒ T cell responses were assessed using intracellular cytokine staining.

Results: Overall, the transmitted virus was highly adapted to the child's anti‐HIV T cell immune potential. The pattern of reversion and fixation of HIV adaptations following transmission was strongly influenced by the HLA‐driven selective environment of the recipient and provided an insight into the replicative capacity cost associated with specific adaptations. Furthermore, there was evidence of de novo post‐transmission adaptation, representing new targets of the child's T cell responses. These de novo adaptations were more likely to occur at sites relevant to paternally inherited HLA alleles compared to sites relevant to the mother's HLA alleles (p = 0.008; mixed‐effects logistic regression); reflecting the transmission network.

Conclusions: HLA‐driven selection pressure is a major contributor to HIV evolution. An understanding of the balance between replicative capacity and immune escape benefit of these adaptations is an important consideration for vaccine and cure strategies for individuals exposed to adapted viruses via transmission or activated from reservoirs.

Item Type: Journal Article
Murdoch Affiliation(s): Institute for Immunology and Infectious Diseases
Publisher: BioMed Central
Copyright: © 2019 The Authors.
Other Information: Conference title: 10th IAS Conference on HIV Science, 21‐24 July 2019, Mexico City, Mexico
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