Differential escape patterns within the dominant HLA-B*57:03-restricted HIV gap epitope reflect distinct clade-specific functional constraints

2014 | J Virol

Program(s): Laboratory |

Abstract:

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.IMPORTANCE SECTION HLA-B*57 is the HLA class I molecule that affords the greatest protection against disease progression in HIV infection. Understanding the key mechanism(s) underlying immune suppression of HIV is of importance in guiding therapeutic and vaccine-related approaches to improve the levels of HIV control occurring in nature. Numerous mechanisms have been proposed to explain the HLA associations with differential HIV disease outcome but no consensus exists. These studies focus on two subtypes of HLA-B*57, prevalent in Caucasian and African populations, HLA-B*57:01 and HLA-B*57:03, respectively. These alleles appear equally protective against HIV disease progression. The CTL epitopes presented are in many cases identical, and the dominant response in chronic infection in each case is to the Gag epitope KF11. However, there the similarity ends. This paper seeks to better understand the reasons for these differences and what this teaches us about which immune responses are contributing to immune control of HIV infection.

BC Centre for Excellence in HIV/AIDS

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Differential escape patterns within the dominant HLA-B*57:03-restricted HIV gap epitope reflect distinct clade-specific functional constraints

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