Functional studies focusing on those relatively rare patients able to spontaneously control HIV-disease progression are key to obtaining insights into the characteristics of CTL responses needed to delay HIV-disease progression. Such studies have previously pinpointed differences in CTL functions between HIV controllers and patients with progressive disease (eg, Refs. 10, 39–46). Our study uniquely compared CTL responses restricted by nonprotective and protective HLA alleles within the same host, such that the effects of slow or rapid progression are not interfering with our readout. Moreover, we analyzed the 2 HLA alleles most convincingly associated with slow disease progression separately, to reveal potential different and/or shared mechanisms of protection. In concordance with previous studies,7,8 we found that the CTL response in individuals coexpressing HLA-B*57 was dominated by CTL against HLA-B*57-binding peptides. In contrast, the CTL response in B*27+ patients was not dominated by CTL against HLA-B*27-binding peptides. In fact, CTL responses restricted by HLA-B*27 and HLA-A*02 were indistinguishable in height and breadth. Moreover, although it has convincingly been shown that CTL specific for the dominant HLA-B*27-restricted epitope KK10 are highly polyfunctional and have a superior functional capacity compared with other HIV-1–specific CTL,10 our data suggest that this is not because of an increased half-life of the interaction between the TCRs and the HLA-B*27–KK10 complex, or the pHLA–B*27 complex in general, indicating that a strong interaction between pHLA complexes and the TCR is not a prerequisite for a protective T-cell response. Thus, although immunodominance, breadth, magnitude, and affinity of the T-cell response might be associated with protection against progression to AIDS in HLA-B*57 expressing individuals, our data show that this is not the case for HLA-B*27.
Our data clearly show that T-cell responses restricted by different HLA molecules influence each other differently, which has also been described for other viruses.37,38 Although the mechanism behind these observed associations is not well understood, this phenomenon has implications for the design of epitope-specific vaccines. In our case, it seems that the effect of HLA-B*27 on the magnitude and breadth of responses restricted through other HLA alleles is because of the beneficial effect of HLA-B*27 on HIV viral load. The low HIV viral load and activation level in patients coexpressing HLA-B*27 might result in a decreased level of exhaustion of all HIV-specific CD8+ T cells, hence also the ones restricted by HLA-A*02 or HLA-B*08. Our findings thereby also illustrate the difficulty in interpreting the quality of CTL responses, as a high and broad (HLA-A*02 or B*08 restricted) CTL response apparently not necessarily means that the HLA in question is driving the favorable clinical outcome.
Our data indicate that there are at least 2 different strategies through which HLA class I alleles can be protective, which include (1) inducing a very dominant CTL response (eg, HLA-B*57) and (2) preservation of total T-cell responses (as observed for HLA-B*27). The marked differences between the 2 protective HLA alleles that we observed are an important new insight, as previous studies often did not distinguish between HLA-B*27 and B*57 when investigating HIV control (eg, Refs. 41, 44–46). Box 1 depicts the observed similarities and discrepancies between HLA-B*27 and B*57, which may contribute to their protective effect. The observation that HLA-B*27 and B*57 exert their protective effect at distinct moments after HIV infection48 suggests the existence of a different mechanism of protection. The effect of HLA-B*57 already occurs early after infection, before the CD4+ T-cell count drops below 200 cells per microliter, whereas HLA-B*27 delays progression to AIDS-defining illnesses when the CD4+ T-cell counts have already dropped below 200 cells per microliter.48 This fits with our observation that the beneficial effect of HLA-B*27 is evident during chronic infection but not early during infection (within 6 months after seroconversion, data not shown).
In conclusion, the actual mechanism(s) of protection offered by an HLA molecule involve both virologic and immunological features. Several virologic features are known,4–6 but the immunological mechanisms are less well understood. We here show that certain mechanisms at least are not required for protection against disease progression. Our data indicate that although HLA-B*57-restricted responses are more likely to be of exceptionally high affinity and downregulate CTL responses restricted through other HLA molecules, HLA-B*27-restricted responses are of moderate affinity, but have a clear beneficial effect on CTL responses restricted by other HLA molecules of the host.
The authors thank Philip Davies for linguistic advice.
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