16th International AIDS Conference Toronto, Canada - August 13 - 18, 2006

HLA-B27-ASSOCIATED CTL ESCAPE MUTATIONS DRAMATICALLY REDUCE VIRAL FITNESS OF HIV-1

Int Conf AIDS. 2006 Aug 13-18;16 Abstract No. TuAa0202

A. Schneidewind¹, M. Brockman¹, R. Adam¹, M. Lahaie¹, C. Brander¹, A. Kelleher², B. Walker¹, T. Allen^1
1 Massachusetts General Hospital, Partners AIDS Research Center, Charlestown, United States, ² National Center in HIV Epidemiology and Clinical Research, Sydney, Australia

BACKGROUND: Growing evidence supports that immune-driven CTL escape mutations compromise HIV-1 replicative capacity, thereby contributing to HLA-associated immune control. Previously we illustrated that escape mutations in the HLA-B57-restricted Gag epitope TW10 reduce viral replication (Conf Retrovir Opportunistic Infect 2005 Feb 22-25;12:abstract no. 448) by increasing susceptibility to host restriction, and impairing binding of the host protein cyclophilin A. We hypothesized that HLA-B27-associated immune control may function through similar mechanisms, by enhancing host restriction susceptibility or altering structurally constrained regions critical for capsid stability. Here we examine the impact of CTL escape mutations within the immunodominant B27-restricted capsid epitope KK10 (KRWIILGLNK) on viral fitness.

METHODS: Using site-directed mutagenesis we have generated a panel of 18 constructs of HIV-1 NL4-3, comprising of a combination of escape and putative compensatory mutations, including the clinically predominant R264K mutant. Variants were examined for their replicative capacity using a GFP-expressing CEM reporter cell line. Capsid production was quantified by p24 ELISA.

RESULTS: The R264K mutation reduced viral progeny production by 15-fold compared to wild-type NL4-3. In 7-day replication assays, the R268K mutant experienced a 60% drop in infected cells as compared to a 2-log increase for wild-type. Exploring the mechanism for this replicative defect we documented a decreased release of viral particles for R264K indicating a possible functional impairment of viral egress. Notably, rarely described escape mutations (R264T, R264Q, and R264G) showed a less dramatic impact on replicative capacity, indicating selection for the highly unfit R264K mutation during KK10 escape. Preliminary data indicates that putative compensatory mutations in p24 can rescue viral fitness defects induced by KK10 escape mutations.

CONCLUSIONS: The selection of high fitness-cost inducing escape mutations within critical regions of HIV-1 capsid may contribute to the immune control associated with HLA-B27. Further insights into the mechanisms of this control will be revealed by analyzing the relationship between escape mutations, viral fitness and host restriction.

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2006-08-13
TuAa0202

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