HIV controllers, though defined by virologic criteria, are typically associated with elevated CD4 cell counts and improved clinical outcomes [6, 7]. We determined that spontaneous virologic suppression in HIV controllers was independent of DTH responsiveness since nearly one-fifth of HIV controllers displayed partial or complete anergy at first DTH testing despite higher CD4 counts, and a similar proportion of non-anergic results were observed between HIV controllers and non-controllers when stratified by CD4 count.
A previous study  in the Air Force component of our HIV-infected population showed that 86% of participants with CD4 count > 400 cells/uL were non-anergic, similar to the 83% and 85% observed for HIV controllers and non-controllers, respectively in our study. Though HIV controllers typically have preserved DTH responses at higher CD4 cell counts, a proportion displayed anergy to recall antigens. Among elite controllers, 26% demonstrated anergy (4 partial and 4 complete) at first DTH testing despite having CD4 cell counts ≥ 400 cells/uL. This suggests that factors contributing to virologic control and DTH responsiveness do not completely overlap. We previously showed that a favorable CCL3L1-CCR5 genetic risk group (GRG) status, which is enriched in the HIV controller population, was associated with greater DTH responsiveness . However, approximately 25% of HIV controllers did not have a favorable CCL3L1-CCR5 GRG status which suggests that elite and viremic controllers may represent a convergence of heterogeneous phenotypes with the common feature of spontaneous virologic control, and reinforces the concept of the presence of both viral load dependent and independent mechanisms of HIV-1 pathogenesis and host response.
In addition to reconstitution of CD4 cells, HAART impacts the immune system in other ways including the improvement of serologic response to vaccinations , reducing immune activation , and enhancing DTH responses [3, 12]. In one study, suppression of plasma viremia was necessary for improved DTH responsiveness on HAART . For HAART-naïve individuals, lower steady-state VL has also been associated with greater DTH responsiveness . In comparison to participants with ≥ 2 years of suppressive HAART in our study, HIV controllers had a greater tendency for non-anergic DTH responses (81.9% vs. 74.5%; P = 0.07) and a similar pattern was observed when stratified by CD4 count. HAART suppressors also displayed less DTH responsiveness than the non-controllers group as a whole. This may be due to enrichment with participants who had declining immune function that led to the initiation of HAART.
Previous studies validated the use of multiple DTH antigen panels for studying various HIV outcomes [1, 2, 9]. Although a similar approach was used, a limitation of our study was that a comparison of individual antigens was not able to be performed. In addition, other virus-related factors that can influence HIV-1 disease progression, such as viral fitness and HIV clade, were not examined. Future studies investigating non-anergic versus anergic DTH responses, including higher resolution ex vivo assays of CMI to recall antigens and other immunologic studies, may provide additional insight into DTH responsiveness.
Although virologic control occurred by different mechanisms, both HIV controllers and HAART suppressors commonly displayed preserved DTH responses, especially at higher CD4 counts. A proportion of HIV controllers were anergic at DTH testing despite higher CD4 cell counts. Thus, HIV controller phenotypes appear to achieve virologic control by disparate mechanisms than those involving DTH responsiveness to recall antigens.