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

UNLABELLED: 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, yet they remain unclear. Unexplained differences are observed in the impact of the dominant cytotoxic T lymphocyte (CTL) response restricted by HLA-B*57:01 and HLA-B*57:03 in chronic infection on the Gag epitope KAFSPEVIPMF (KF11; Gag 162 to 172). We previously showed that the HLA-B*57:03-KF11 response is associated with a >1-log-lower viral setpoint in C clade virus infection and that this response selects escape mutants within the epitope. We first examined the relationship of KF11 responses in B clade virus-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 >1,800 B clade virus-infected subjects. We then studied a B clade virus-infected cohort in Barbados, where HLA-B*57:03 is highly prevalent. In contrast to findings for B clade virus-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 CTLs 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: 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 immunosuppression 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 study sought to better understand the reasons for these differences and what they teach us about which immune responses contribute to immune control of HIV infection.

CD8αα Expression Marks Terminally Differentiated Human CD8+ T Cells Expanded in Chronic Viral Infection.

The T cell co-receptor CD8αß enhances T cell sensitivity to antigen, however studies indicate CD8αα has the converse effect and acts as a co-repressor. Using a combination of Thymic Leukemia (TL) antigen tetramer, which directly binds CD8αα, anti-CD161, and anti-Vα7.2 antibodies we have been able for the first time to clearly define CD8αα expression on human CD8 T cells subsets. In healthy controls CD8αα is most highly expressed by CD161 "bright" (CD161++) mucosal associated invariant T (MAIT) cells, with CD8αα expression highly restricted to the TCR Vα7.2+ cells of this subset. We also identified CD8αα-expressing populations within the CD161 "mid" (CD161+) and "negative" (CD161-) non-MAIT CD8 T cell subsets and show TL-tetramer binding to correlate with expression of CD8ß at low levels in the context of maintained CD8α expression (CD8α+CD8ß(low)). In addition, we found CD161-CD8α+CD8ß(low) populations to be significantly expanded in the peripheral blood of HIV-1 and hepatitis B (mean of 47 and 40% of CD161- T cells respectively) infected individuals. Such CD8αα expressing T cells are an effector-memory population (CD45RA-, CCR7-, CD62L-) that express markers of activation and maturation (HLA-DR+, CD28-, CD27-, CD57+) and are functionally distinct, expressing greater levels of TNF-α and IFN-γ on stimulation and perforin at rest than their CD8α+CD8ß(high) counterparts. Antigen-specific T cells in HLA-B(∗)4201+HIV-1 infected patients are found within both the CD161-CD8α+CD8ß(high) and CD161-CD8α+CD8ß(low) populations. Overall we have clearly defined CD8αα expressing human T cell subsets using the TL-tetramer, and have demonstrated CD161-CD8α+CD8ß(low) populations, highly expanded in disease settings, to co-express CD8αß and CD8αα. Co-expression of CD8αα on CD8αß T cells may impact on their overall function in vivo and contribute to the distinctive phenotype of highly differentiated populations in HBV and HIV-1 infection.