Volume 9 Supplement 2

AIDS Vaccine 2012

Open Access

Limited evidence for alterations in Gag-mediated HIV replication capacity over the course of the North American epidemic (1979-present)

  • L Cotton1,
  • D Chopera1,
  • K Penney1,
  • J Carlson2,
  • E Martin1,
  • A Le1,
  • T Kuang1,
  • B Walker3,
  • J Fuchs4,
  • S Buchbinder4,
  • T Wagner4,
  • M John5,
  • S Mallal5,
  • B Koblin6,
  • K Mayer7,
  • A Poon8,
  • M Brockman1 and
  • Z Brumme1
Retrovirology20129(Suppl 2):P157

DOI: 10.1186/1742-4690-9-S2-P157

Published: 13 September 2012

Background

The extent to which HIV replication capacity (RC) has changed over the epidemic’s course, and the influence of HLA-associated immune pressure as its driving force remains unknown. We performed a comparative study of immune escape and RC in historic (1979-1989) and modern Gag subtype B sequences from North America.

Methods

Using phylogenetically-informed methods, we identified HLA-associated Gag polymorphisms in a historic cohort (N=239; 1979-1989). We also generated recombinant NL4-3 viruses encoding clonal plasma RNA Gag from 80 historic and 58 modern (2002-2008) sequences. Viral RC was measured using a GFP reporter T-cell assay and results were normalized to NL4-3 controls.

Results

95% of HLA-associated polymorphisms identified in the historic cohort were consistent with published modern escape pathways. Overall, the prevalence of HLA-associated polymorphisms in the general population increased a median 1.3-fold between historic and modern sequences; however in many cases this was influenced by differences in HLA allele frequencies between HIV-infected populations examined. Of note, the prevalence of the B*27-associated R264K escape mutation increased from 0.4 to 1.3% in the general population over time despite B*27 allele frequency remaining constant at 2.5%. Modestly lower viral RC was observed for Gag recombinant viruses constructed from pre-1985 sequences (median 0.86 [IQR 0.78-0.97], N=24) compared to those from 1985-1989 (median 0.98 [IQR 0.87-1.05], N=56) and 2002-2008 (median 0.96 [IQR 0.83-0.1.10], N=58) (p=0.049). In both historic and modern cohorts, host expression of HLA-B*27 was associated with lower RC (p=0.007). Gag codons associated with lower RC, including S67A, were identified in an exploratory analysis.

Conclusion

Gag-mediated viral RC may have increased modestly since the beginning of the North American epidemic, despite limited evidence for HLA-driven viral sequence evolution during this time. Although mechanisms driving RC differences remain unclear, results do not support rapid and substantial accumulation of HLA-driven escape mutations in circulating North American HIV-1 sequences.

Authors’ Affiliations

(1)
Simon Fraser University
(2)
Microsoft Research
(3)
Ragon Institute
(4)
San Francisco Dept of Public Health
(5)
Murdoch University
(6)
New York Blood Center
(7)
Fenway Community Health
(8)
BC Centre for Excellence in HIV/AIDS

Copyright

© Cotton et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement