Several recent studies have suggested that qualitative characteristics of the HIV-1-specific T cell are associated with protection, viral control, and rate of disease progression 
. To our knowledge this is the first study to compare the qualitative characteristics of total CD8+ and CD4+ as well as HIV-specific T cell responses in perinatally infected children with different levels of disease progression, with a significant finding relating specific CD4+ T cell profiles with disease progression rate. Moreover, unlike previous studies which have focused on individuals of Northern European descent, this work concentrated primarily on African Americans and Hispanics.
The children in this study, all older than 10 years of age and thus considered long-term survivors (LTS), were categorized, based on CD4+ T cell percentage levels, into those with no immune suppression (LTS-NS) and those with severe immune suppression (LTS-SS), based on previously published CDC guidelines 
. We observed a highly significant increase in the frequency of naïve CD8+ T cells (TNAIVE
) in the LTS-NS subjects (p
0.0066), compared to the LTS-SS subjects, but no differences in any other CD8+ T cell subsets. The differentiation profiles of Gag-specific CD8+ T cells were similar between the progression groups.
The most striking finding of this study was the CD4+ T cell differentiation profiles between the two progression groups. Subjects in the LTS-NS group had significantly higher levels of naïve T cells (TNAIVE
) and central memory (TCM
) CD4+ T cells than LTS-SS children (
0.0005 and p<0.0001, respectively). In contrast, children in the LTS-SS group had significantly higher levels of effector memory RA+ (TEMRA
) cells (p<0.0001). These data suggest that disease progression in these vertically infected younger patients is different than adults and is associated with a shift towards greater TEMRA
The shift towards greater TEMRA
cells could represent a disproportionate loss of certain T cell subsets in LTS-SS subjects consistent with published data. A recent study showed that CD4+ cells with the TEMRA
phenotype (CCR7−CD45RA+) were more prevalent in HIV-1-infected individuals than in uninfected controls 
. They described that these cells were resistant to in vitro
infection by CCR5-tropic strains of HIV-1, despite robust expression of CCR5. Loss of Naïve T cells was also observed in a study of HIV infected infants. In this study, there was an association between rapid disease progression and decreases in naïve cells but with little effect on memory cells. The loss of naïve cells appeared to be mediated through thymic dysfunction 
. Our cohort consists of long term survivors of vertically acquired HIV-1 infection who were infected perinatally. The loss of naïve and central memory cells and increased frequency of TEMRA
cells could therefore be due to a combination of a greater susceptibility to HIV-1 related cell death, together with thymic dysfunction. Future studies would need to address the relative contributions of these conditions to the observations.
The greater susceptibility of naïve and central memory T cells to loss could potentially be due to effects of chronic immune stimulation from HIV-1. Additional studies would also benefit from analyses looking at cell surface activation markers such as CD38 or HLA-DR. The loss of naïve and central memory T cells, with the accumulation of TEMRA cells, suggests altered T cell maturation kinetics or a change in TEMRA lifespan in progressing subjects. We observed a greater frequency of CD4+CD57+ cells in the LTS-SS group that correlated negatively with CD4% and positively with viremia. CD57 is a marker of senescence. The relationship of the increased CD57+ frequency with other markers of disease progression corroborates the proposed detrimental effect of maturation. This suggests an inability of homeostatic mechanisms to maintain the appropriate proportion of T cell phenotypes necessary for HIV-1 control in progressing subjects and could be related to the accumulation of TEMRA cells.
This study suggests that T cell maturation patterns are significantly different in perinatally HIV-1-infected children with different levels of disease progression, but there are some caveats to be considered. The relatively small number of subjects in the study precludes us from applying these findings to a general pediatric population. The subjects were not all on the same antiretroviral treatment regimens. However, we attempted to minimize these concerns by choosing subjects for the study who: 1) did not receive 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. Another equalizing factor is that both groups, as a whole, had generally similar treatment adherence rates. We also cannot be completely confident that the staining protocol does not potentially alter the pattern of staining of CD4+ T cells, which would be avoided by staining antigen specific cells with tetramers. However, few class II tetramers are now available for such studies.
We observed an extremely strong correlation between increased CD4+ TEMRA cells and more severe immunological suppression. Although this suggests that these cells are accumulating during progressive infection, more research into this area is needed. The previously observed resistance of these terminally differentiated cells to R5 tropic strains of HIV-1 is intriguing and may be part of the explanation why these patients are long-term survivors despite persistently low CD4+ T cell levels. These findings could be of importance to the field of pediatric HIV-1 immunology as well as the larger field of HIV-1 vaccine design.