Differential escape patterns within the dominant HLA-B*57:03-restricted HIV gag epitope reflect distinct Clade-Specific functional constraints
Payne, R.P., Branch, S., Kloverpris, H., Matthews, P.C., Koofhethile, C.K., Strong, T., Adland, E., Leitman, E., Frater, J., Ndung'u, T., Hunter, E., Haubrich, R., Mothe, B., Edwards, A., Riddell, L., Chen, F., Harrigan, P.R., Brumme, Z.L., Mallal, S., John, M., Jooste, J.P., Shapiro, R., Deeks, S.G., Walker, B.D., Brander, C., Landis, C., Carlson, J.M., Prado, J.G. and Goulder, P.J.R. (2014) Differential escape patterns within the dominant HLA-B*57:03-restricted HIV gag epitope reflect distinct Clade-Specific functional constraints. Journal of Virology, 88 (9). pp. 4668-4678.
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HLA-B*57:01 and HLA-B*57:03, the most prevalent HLA-B*57 subtypes in Caucasian and African populations, respectively, are the HLA alleles most protective against HIV disease progression. Understanding the mechanisms underlying this immune control is of critical importance and yet remains unclear. Unexplained differences are observed in the impact of the dominant CTL response restricted by HLA-B*57:01 and HLA-B*57:03 in chronic infection towards the Gag epitope KAFSPEVIPMF (‘KF11’ ,Gag162-172). We previously showed that the HLA-B*57:03-KF11 response is associated with a >1 log lower viral setpoint in C-clade infection and that this response selects escape mutants within the epitope. We first examined the relationship of KF11 responses in B-clade infected subjects with HLA-B*57:01 to immune control and observed that a detectable KF11 response was associated with a >1 log higher viral load (p=0.02). No evidence of HLA-B*57:01-KF11 associated selection pressure was identified in previous comprehensive analyses of >1800 B-clade infected subjects infected. We then studied a B-clade infected cohort in Barbados where HLA-B*57:03 is highly prevalent. In contrast to B-clade infected subjects expressing HLA-B*57:01, we observed strong selection pressure driven by the HLA-B*57:03-KF11 response for the escape mutation S173T. This mutation reduces recognition of virus-infected cells by HLA-B*57:03-KF11 CTL, and is associated with a >1 log increase in viral load in HLA-B*57:03-positive subjects (p=0.009). We demonstrate functional constraints imposed by HIV clade relating to the residue at Gag-173 that explain the differential clade-specific escape patterns in HLA-B*57:03 subjects. Further studies are needed to evaluate the role of the KF11 response in HLA-B*57:01-associated HIV disease protection.
|Publication Type:||Journal Article|
|Murdoch Affiliation:||Institute for Immunology and Infectious Diseases|
|Publisher:||American Society for Microbiology|
|Copyright:||© 2014 American Society for Microbiology|
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