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Sites and kinetics of HLA-associated immune escape in HIV-1 integrase

Brumme, Z.L., Rosato, P., Sela, J., Brumme, C.J., Brockman, M.A., John, M., Carlson, J.M., Baker, B.M., Streeck, H., Swenson, L., Chan, D., Markowitz, M., Jessen, H., Kelleher, A., Rychert, J., Rosenberg, E., Allen, T., Altfeld, M., Berger, C.T., Frahm, N., Brander, C., Harrigan, P.R., Mallal, S., Heckerman, D. and Walker, B.D. (2009) Sites and kinetics of HLA-associated immune escape in HIV-1 integrase. In: 5th IAS Conference on HIV Pathogenesis and Treatment and Prevention, 19 - 22 July 2009, Cape Town, South Africa.


Background: Acute-phase CTL responses, and the virus' ability to escape from them, shape the clinical course of HIV-1 disease. Elucidating early within-host viral evolution is key to our understanding of HIV pathogenesis. Using population-level data, the locations and kinetics of HLA-associated escape mutations in Gag, protease/RT and Nef have been identified. Here we extend these observations by characterizing sites and kinetics of escape and reversion in integrase.

Methods: HLA-associated integrase polymorphisms were defined in a cross-sectional analysis of >1200 antiretroviral naïve, chronically HIV-1 subtype B-infected individuals. Using Kaplan-Meier methods, rates of HLA-associated escape and reversion at these sites were calculated in a seroconverter cohort (N=98) for whom longitudinal plasma RNA genotyping of integrase was performed in the first year of infection. CTL recognition frequencies of optimally-described epitopes and integrase-wide overlapping peptides (OLP) were assessed by IFN-γ ELISpot in independent cohorts of acute/early (N=289) and chronically-infected (N=372) individuals, respectively.

Results: We identified >100 HLA-associated polymorphisms occurring at 62 integrase codons. Of these, >45% fell within published or putative epitopes (identified by OLP responses and bioinformatic predictions). Over 400 pairwise amino acid associations were identified, illuminating potential compensatory pathways. Longitudinal data from seroconverters revealed evidence of escape within ~50% of published and putative epitopes within the first year of infection. Epitope B*57-SW10 escaped most rapidly, at a rate comparable to B*57-TW10-Gag, despite a lower recognition frequency in acute/early infection. B*44-QW11, B*58-SW10, B*51-LI9 and putative B*27-KY10 also escaped relatively rapidly. Overall, a minimum of ~20-30% of integrase substitutions in the first year post-infection were attributable to escape/reversion.

Conclusions: Immune escape occurs in integrase in the first year of infection, confirming this protein as an early target by CTL. These results extend our understanding of the earliest immune-driven viral adaptation events occurring in vivo.

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