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Reversion of HLA-Associated Polymorphisms in GAG, POL and NEF during the first year of HIV infection: Sites, Rates and pVL correlations

Brumme, C.J., Brumme, Z.L., Carlson, J., Markowitz, M., Jensen, H., Kelleher, A., John, M., Mallal, S., Allen, T., Heckerman, D. and Walker, B.D. (2008) Reversion of HLA-Associated Polymorphisms in GAG, POL and NEF during the first year of HIV infection: Sites, Rates and pVL correlations. In: AIDS Vaccine 2008, 13 - 16 October, Cape Town, South Africa.


Background: Replicative fitness costs of CTL escape mutations are suggested by reversion upon transmission to HLA-unmatched hosts, however rates of reversion and the clinical significance of acquired escape mutations remain incompletely characterized. Here we identify the most rapidly reverting codons in Gag, Pol and Nef and correlate the number of HLA-mismatched CTL escape mutations with pVL setpoint.

Methods: A list of HLA-associated HIV polymorphisms was predefined in an independent analysis of a large chronic untreated cohort (N>1200). Frequencies and rates of reversion of transmitted HLA-associated Gag/Pol/Nef substitutions in hosts not bearing the given HLA allele were calculated in a longitudinal, untreated, subtype-B-infected cohort (N¼98) identified in acute/ early infection over a median 14 months follow-up. The relationship between the presence of acquired HLA-mismatched polymorphisms and pVL setpoint was investigated using Spearman’s rank correlation.

Results: Inferred reversions were observed at 38 (8%), 21 (4%) and 36 (17%) Gag, Pol and Nef codons respectively; the majority (65%) within published CTL epitopes. Reversions within Gag epitopes restricted by protective HLA alleles (B*13, B*51, B*57, B*58) occurred more rapidly than reversions outside these regions (p¼0.02). Among the most rapidly reverting Gag mutations were B*57-associated escape mutations at codons 147 and 242 in the IW9 and TW10 epitopes respectively. We observed no significant correlation between the number of acquired HLA-mismatched CTL escape mutations, and pVL setpoint measured at one year post-infection. No significant differences in pVL were observed when restricting to escape mutations within CTL epitopes, or mutations selected by protective HLA alleles.

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