Potential Role for HIV-Specific CD38⁻/HLA-DR⁺ CD8⁺ T Cells in Viral Suppression and Cytotoxicity in HIV Controllers

<div><p>Background</p><p>HIV controllers (HIC) are rare HIV-1-infected patients who exhibit spontaneous viral control. HIC have high frequency of CD38⁻/HLA-DR⁺ HIV-specific CD8⁺ T cells. Here we examined the role of this subset in HIC status.</p><p>Materials and Methods</p><p>We compared CD38⁻/HLA-DR⁺ CD8⁺ T cells with the classical CD38⁺/HLA-DR⁺ activated phenotype in terms of 1) their activation status, reflected by CD69, CD25, CD71, CD40 and Ki67 expression, 2) functional parameters: Bcl-2 expression, proliferative capacity, and IFN-γ and IL-2 production, and 3) cytotoxic activity. We also investigated how this particular profile is generated.</p><p>Results</p><p>Compared to CD38⁺/HLA-DR⁺ cells, CD38⁻/HLA-DR⁺ cells exhibited lower expression of several activation markers, better survival capacity (Bcl-2 MFI, 367 [134–462] vs 638 [307–747], <i>P</i> = 0.001), higher frequency of polyfunctional cells (15% [7%–33%] vs 21% [16%–43%], <i>P</i> = 0.0003), greater proliferative capacity (0-fold [0–2] vs 3-fold <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101920#pone.0101920-Lambotte1" target="_blank">[2]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101920#pone.0101920-Migueles2" target="_blank">[11]</a>, <i>P</i> = 0.007), and higher cytotoxicity <i>in vitro</i> (7% [3%–11%] vs 13% [6%–22%], <i>P</i> = 0.02). The CD38⁻/HLA-DR⁺ profile was preferentially generated in response to low viral antigen concentrations.</p><p>Conclusions</p><p>These data highlight the role of CD38⁻/HLA-DR⁺ HIV-specific CD8⁺ T cell cytotoxicity in HIC status and provide insights into the mechanism by which they are generated. Induction of this protective CD8⁺ subset may be important for vaccine strategies.</p>