Our results show that higher frequencies of HIV-specific TEM57− CD8 T cells are associated with spontaneous control of HIV replication in EC and suggest that the maintenance of these cells is important in controlling HIV infection. In addition, these data argue that it is important to maintain HIV-specific Mem57− CD4 cells during HIV infection; these cells most likely play an important role in support of the TEM57− CD8 T cell population.
The lack of HIV-specific proliferative CD4 cell responses is a hallmark of progressive HIV infection (14
). Our data confirm and extend the observations of others which have shown that individuals who are able to spontaneously control HIV replication are more likely to have a high frequency of HIV-specific CD4 T cells that produce IL-2 when stimulated. Production of IL-2 by CD4 T cells has consistently been associated with increased replicative capacity. In contrast, we found no difference in CMV-specific CD4+
T cell responses between controllers and NC, with CMV infection being controlled by both groups of individuals in our cohort. The EC and RC groups had the same frequency of HIV-specific CD8+
T cells (90%). However, EC had more HIV-specific CD4 T cells (89%) than RC (64%), thus revealing differences in HIV-specific responses between the EC and RC groups. It should be noted that while EC and RC always had an HIV-specific CD4 and/or CD8 cell response, 30% of the NC individuals completely lacked measurable HIV-specific T cells. This straightforward analysis shows the importance of T cell responses in HIV replication control.
Not only did EC have a higher magnitude of HIV-specific CD4 T cell response than RC, but they also had more polyfunctional T cells with a particular maturation phenotype. In agreement with this result, Emu et al. (8
) previously reported that lower VLs (VLs of <10,000 RNA copies/ml in untreated or highly active antiretroviral therapy [HAART]-treated, partially suppressed individuals) were associated with higher percentages of memory CD4 T cells. For the HIV controller scenario, Potter et al. (21
) compared RC subjects (defined as those having HIV VLs of <400 RNA copies/ml) to NC and found similar rates of IFN-γ-producing HIV-specific CD4 T cells in both groups. They also showed that p24-specific central memory (CD45RA−
) and effector memory (CD45RA−
) CD4 T cells from RC showed higher frequencies of IL-2 production than similar cells from NC. We extended these results by showing that HIV-specific CD4 T cells are increased in EC compared to RC. Our study extends this interesting work by demonstrating a greater effect in EC, which strongly suggests the importance of retaining a relatively immature phenotype in the CD4 T cell subset for the spontaneous control of HIV replication.
In contrast to our results, Addo et al. (1
) reported that terminally differentiated (CD45RA+
) HIV-specific cells are increased preferentially in RC compared to NC. Our data show that it is the CD27−
HIV-specific response that is increased significantly in controllers. This increase results in a more effective polyfunctional response (4
). We saw no difference between the functional responses of NC, RC, and EC for the CD27−
population. In addition, we saw no significant difference in the frequency of the CD27−
T cell response in these groups. Several differences in experimental design could contribute to this difference. Addo et al. did not use asymptomatic viremic progressors as we did, and they also used different maturation markers. In addition, Addo et al. used single peptides, whereas we used pooled consensus Gag 15-mers overlapping by 11 amino acids.
In a recent study, a new functional feature of EC, i.e., rapid secretion of perforin (PRF1), was related to viral load control. Hersperger et al. (11
) reported PRF1 level differences between EC and chronic progressors (CP), while EC and RC had similar Gag-specific PRF1 expression. Like Hersperger et al. (11
), we included both surface mobilization of CD107a and increased PRF1 production as markers of cytolytic activity to determine whether subsets with different maturation patterns also showed enhanced cytotoxicity. Mature HIV-specific CD8 T cells from EC, but not CMV-specific T cells, showed an increase in the IFN-γ+
triple-positive subset, suggesting that more mature HIV-specific CD8 T cells have higher cytotoxic abilities. However, we observed no differences in isolated PRF1 expression among our HIV groups. Hersperger et al. set their cutoff for CP as a load of >10,000 RNA copies/ml (9
), while we set our cutoff at >2,000 RNA copies/ml. A limitation of our study is the modest number of EC analyzed (n
= 9), since these patients, representing less than 1% of the overall total of HIV-infected patients, are difficult to recruit. Therefore, the lack of differences observed in the current study could be related to small sample numbers, and increased PRF1 levels may be detected in a larger cohort.
Despite the need for further longitudinal studies to establish whether these maturation phenotypes are the cause or consequence of the spontaneous control of viremia, our results strongly suggest that less mature HIV-specific “central memory-like” CD4+ T cells, by providing the required T cell help for optimal maturation of the “effector memory-like” HIV-specific T cell population, play an important role in the control of HIV replication. Immunotherapeutic trials should attempt to foster conditions which result in the production and maintenance of these cell types.