Several studies have suggested that qualitative characteristics of the HIV-1-specific CD8+ T cell response are associated with viral control and disease progression 
. Other studies have suggested that immunodominance patterns of HIV-1-specific CD8+ T cell responses are of great importance in establishing control of the virus and HIV-1 disease 
. We observed no difference in the magnitude or breadth of the Gag-specific CD8+ T cell response between the two groups, as measured by IFN-γ production, consistent with other studies 
. In contrast, there were several differences in the epitope regions of Gag that were targeted by CD8+ T cell responses. In bulk CD8+ T cell populations we observed a significantly higher frequency of naïve CD8+ T cells in the NS subjects (p
0.0066) compared to the SS subjects, but no differences in any other CD8+ T cell subsets. The differentiation profiles and multifunctional capacity of Gag-specific CD8+ T cells, regardless of immunodominance, were similar between the progression groups. Together, these data suggest that, at least in perinatally infected adolescents, the region of Gag targeted by CD8+ T cells may have more importance to the rate of disease progression than qualitative features such as differentiation and multifunctionality.
There have been conflicting reports on the association between the breadth of the Gag-specific response and disease progression. Early studies showed a negative association between the breadth of the HIV-1-specific response and disease progression 
, while other studies have observed no relationship 
. Other investigations have found that individuals with putative protective HLA alleles have CD8+ T cell responses that predominantly target specific regions within the Gag protein during acute infection 
. These data suggest that the overall breadth of response is not as important as which epitopes are targeted, specifically those regions in Gag that are restricted by protective alleles.
The peptide (5029) which was significantly targeted more frequently by NS relative to SS subjects (44% vs. 13.6%), contains the TL9 (TPQDLNTML) epitope, which has previously been identified as a peptide frequently targeted by HLA-B*42 restricted CD8+ T cell responses 
. The TL9 epitope shares significant homology to the Mamu-A*01-restricted epitope CM9 (CTPYDINQM), which has been implicated in viral control in SIV-infected macaques 
. This suggests that recognition of this area of Gag could be important in establishing immune responses that might be contributing to the slow disease progression in perinatally infected adolescents.
Of the various MHC Class I alleles in this study cohort, only HLA-B*57 and B*42 overwhelmingly restricted immunodominant responses in that 100% of subjects with at least one copy of these alleles restricted their immunodominant response through that allele. Interestingly, these two alleles occurred much more frequently within the NS group, suggesting that the immune response directed through these alleles plays a role in mediating slower disease progression. This finding is consistent with the effect of the HLA-B*57 allele on slow disease progression in adults 
, but has not been demonstrated in a perinatally infected population. HLA-B*42-restricted responses have been noted for their immunodominance in a population with African ancestry 
, but have not previously been associated with slower disease progression.
Although this study suggests that immunodominance patterns are a critical component in the disease progression of perinatally HIV-1-infected adolescents, several caveats remain. The small number of subjects precludes us from applying these findings to the general HIV-1 infected pediatric population. These patients were not all receiving the same treatment regimen, but this is an inherent concern in studies where the subjects are drawn from heterogeneous clinic populations. We attempted to minimize this concern, by choosing subjects for the study who: 1) had not received HAART in the first two years of life; 2) had some levels of ongoing viral replication; and 3) were ARV-experienced (except for two patients). Both groups had generally similar treatment adherence rates to antiretroviral drugs, and variable adherence to ART is common in HIV-1 infected adolescents. We used the HXB-2 peptide set from the NIH as antigens, and this may both underestimate and potentially miss autologous epitopic responses. As we were limited with cell numbers, we focused on the HIV-1 Gag antigen, and responses to other HIV-1 proteins are important to consider 
Our study was well balanced overall for age with a range from 10 to 18 years between the 2 groups studied. Age of the subject could be contributing to the pattern of immunodominance. However, the age range is relatively narrow with most subjects developmentally considered adolescents. Therefore, age was considered to be less unlikely to yield meaningful relationships to immunodominance patterns and therefore no formal testing for the effect of age was conducted.
This study is one of the first to study the patterns of immunodominance and associations with disease progression in a cohort of perinatally infected adolescents. Moreover, this work focused on African American and Hispanic children, two populations that are greatly underrepresented in studies on the HIV-1-specific immune response. We find that in adolescents, as in adults 
, the immunodominance patterns appear to influence rates of disease progression. This influence seems to be mainly focused on the exquisite targeting of certain Gag epitopes, and not on the differentiation or cytokine secretion profiles of antigen-specific CD8+ T cells. These findings may be of importance to the field of pediatric HIV-1 immunology as well as the larger field of HIV-1 vaccine design.