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Molecular and functional consequences of immune-mediated evolution in HIV-1 Nef during the North American epidemic.

Brumme, C.J., Chan, B., Markle, T., Carlson, J., Martin, E., Le, Q.A., Penney, K., Rahman, M., Kuang, T., Nassab, P., Chopera, D.R., Markowitz, M., John, M., Mallal, S., Walker, B.D., Koblin, B., Mayer, K., Brockman, M.A., Poon Art, F.Y. and Brumme, Z.L. (2011) Molecular and functional consequences of immune-mediated evolution in HIV-1 Nef during the North American epidemic. In: AIDS Vaccine 2011, 12–15 September, 2011, Bangkok, Thailand.

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Background: HLA-restricted CTL responses drive evolution of the highly immunogenic Nef protein, but the extent and functional consequences of population-level adaptation remain unclear. We have used novel historic Nef data to estimate the date and reconstruct the founder virus sequence of the North American epidemic, compare patterns of population-level HLA-associated
polymorphisms over time, and assess CD4 downregulation activity of historic and modern Nef sequences.
Methods: Plasma HIV-1 RNA Nef sequencing and HLA typing was performed on 241 historic specimens (1979–89). Modern published HLA/HIV datasets served as controls. Timing and sequence reconstruction of the founder Nef was performed using BEAST and HyPhy. HLA-associated polymorphisms were identified using phylogenetically-corrected methods. CD4 downregulation capacity of 52 historic vs. 52 modern Nef sequences was compared using flow cytometric methods.
Results: Based on Nef sequences, the most recent common ancestor of the North American epidemic was dated to 1965. The consensus of the reconstructed founder Nef sequence differed from 2004 subtype B consensus at codons 15, 22, 51 and 178, while additional sites remained ambiguous in the reconstruction. Patterns
and statistical strengths of HLA-associated polymorphisms remained generally consistent over time (e.g. A*24-associated Y135F, B*07-R71K, B*08-K94Q and B*57-H116N ranked among the strongest in historic and modern cohorts); however, a small number of polymorphisms were identified as candidates for population-level accumulation. Functional assessment of Nef revealed a modest yet statistically significant increase in CD4 downregulation capacity over time (median 0.93 vs. 1.00 in historic vs. modern sequences; p = 0.005).
Conclusion: Modest population-level immune adaptation in Nef, potentially leading to modest increases in CD4 downregulation capacity, may have occurred in North America since 1979. However, the relatively high similarity between the estimated founder and modern consensus B, and the observation that CTL escape patterns have remained largely consistent over time, support Nef as a suitable target for vaccine consideration.

Item Type: Conference Item
Murdoch Affiliation(s): Institute for Immunology and Infectious Diseases
Publisher: Mary Ann Liebert
Copyright: ©2012 Mary Ann Liebert, Inc.
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