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HIV-1 adaptation to early HLA restricted immune responses in acute heterosexual transmission

Keane, N.M., Pfafferott, K., Cooper, D., Roberts, S.G., Chopra, A., Demaine, E., Krishnan, T., Mallal, S. and John, M. (2010) HIV-1 adaptation to early HLA restricted immune responses in acute heterosexual transmission. In: 22nd Annual Conference of the Australasian Society for HIV Medicine, 20 - 22 October 2010, Sydney, Australia


The immune responses which drive the earliest selection of viral adaptations in heterosexual transmission provide insights into the responses most important for acute natural control of founder viruses, which should be harnessed by preventative vaccines. Similarly, those viral adaptations which revert early after transmission will reflect sites of strong constraint against escape from natural and vaccine-induced responses. Here we characterize in detail the virological and immunological events in an individual who presented with HIV (subtype A) infection only days after epidemiologically proven sexual transmission, and pre-seroconversion (Fiebig stage II). Quantitative changes to intra-patient viral sequences were evaluated with deep pyrosequencing of full-length HIV-1 genomes in both donor and recipient.

Longitudinal Sanger and FLX 454 sequencing of HIV-1 was performed on 8 plasma samples from day 13 to 467 post-transmission. HIV-specific CD8 T cell responses were evaluated in 9 PBMC samples (day 35-656) using HLA-class 1 matched peptides in the IFNg ELISpot assay. The donor and recipient shared an HLA-C allele (HLA-C*04) but were discordant at all other HLA class I loci. Evolution of escape in an immunodominant HLA-B*1503-restricted Nef WL9 epitope was detected on day 264 and was present in 41% of viral quasi-species at day 264. T cell responses were detected prior to sequence change and decreased thereafter. Sequence change and CD8 T cell responses were also detected in relation to other published HLA-restricted epitopes. However, early reversion and subsequent re-selection was observed at position 133 of Nef which is not within a known epitope but corresponded to a HLA-C*0401 associated polymorphism in population-based studies. Overall, IFNg responses were detected to 3 of 28 HIV-1 peptides tested on day 35 but broadened to 20 responses while infection became established and reached peak viral load on day 383. T cell responses declined after commencement of antiviral therapy.

Adaptive viral changes and reversions in early HIV-1 infection occur at novel sites not captured in immunological studies of chronically infected individuals. This data suggests the presence of novel immune hierarchies and escape mutations in early infection, which may be applied to HIV vaccine design against founder viruses.

Item Type: Conference Paper
Murdoch Affiliation(s): Centre for Clinical Immunology and Biomedical Statistics
Institute for Immunology and Infectious Diseases
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