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Application of a case–control study design to investigate genotypic signatures of HIV-1 transmission

Talia M Mota12, John M Murray34, Rob J Center1, Damian F J Purcell1* and James M McCaw56*

Author Affiliations

1 Department of Microbiology and Immunology, University of Melbourne, Parkville, VIC 3010, Australia

2 Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Parkville, VIC 3010, Australia

3 School of Mathematics and Statistics, University of New South Wales, Sydney, NSW 2052, Australia

4 The Kirby Institute, University of New South Wales, Sydney, NSW 2052, Australia

5 Vaccine and Immunisation Research Group, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3010, Australia

6 Melbourne School of Population Health, The University of Melbourne, Parkville, VIC 3010, Australia

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Retrovirology 2012, 9:54  doi:10.1186/1742-4690-9-54

Published: 25 June 2012

Abstract

Background

The characterization of HIV-1 transmission strains may inform the design of an effective vaccine. Shorter variable loops with fewer predicted glycosites have been suggested as signatures enriched in envelope sequences derived during acute HIV-1 infection. Specifically, a transmission-linked lack of glycosites within the V1 and V2 loops of gp120 provides greater access to an α4β7 binding motif, which promotes the establishment of infection. Also, a histidine at position 12 in the leader sequence of Env has been described as a transmission signature that is selected against during chronic infection. The purpose of this study is to measure the association of the presence of an α4β7 binding motif, the number of N-linked glycosites, the length of the variable loops, and the prevalence of histidine at position 12 with HIV-1 transmission. A case–control study design was used to measure the prevalence of these variables between subtype B and C transmission sequences and frequency-matched randomly-selected sequences derived from chronically infected controls.

Results

Subtype B transmission strains had shorter V3 regions than chronic strains (p = 0.031); subtype C transmission strains had shorter V1 loops than chronic strains (p = 0.047); subtype B transmission strains had more V3 loop glycosites (p = 0.024) than chronic strains. Further investigation showed that these statistically significant results were unlikely to be biologically meaningful. Also, there was no difference observed in the prevalence of a histidine at position 12 among transmission strains and controls of either subtype.

Conclusions

Although a genetic bottleneck is observed after HIV-1 transmission, our results indicate that summary characteristics of Env hypothesised to be important in transmission are not divergent between transmission and chronic strains of either subtype. The success of a transmission strain to initiate infection may be a random event from the divergent pool of donor viral sequences. The characteristics explored through this study are important, but may not function as genotypic signatures of transmission as previously described.

Keywords:
HIV-1; Transmission; Envelope protein; α4β7; Glycosites; Variable loops; Case–control study; Histidine; Chronic infection