Background:  The HIV-mediated immune response may be both beneficial or harmful, depending on the balance between expansion of HIV-specific T cells and the level of generalized immune activation. Here, we investigate the steady-state balance between these factors in patients with progressive and non-progressive HIV disease, and determine to what degree this balance is altered in patients with drug-resistant HIV. 

Methods:  The proportion of HIV-specific IL-2 and interferon-γ-producing T cells and the proportion of proliferating (Ki67) and activated (CD38⁺) T cells were measured using multiparameter flow cytometry. Three groups of patients were studied:  13 long-term non-progressors (LTNP), 28 subjects with low-level drug-resistant viremia in the presence of therapy (partial controllers on antiretroviral therapy [PCAT]), and 25 with high-level viremia (progressors). 

Results:  Compared with progressors, LTNP exhibited higher frequencies of HIV-specific IL-2⁺IFN-γ⁺ CD4⁺ T cells (p = 0.002), and higher frequencies of HIV-specific IFN-γ bright CD8⁺ and CD4⁺ T cells (p = 0.02 for CD8⁺ and p = 0.03 for CD4). LTNP also exhibited a small but consistent number of HIV-specific IL-2⁺ CD8⁺ T cells (p < 0.001). The presence of HIV-specific CD4⁺IL-2⁺ T cells was associated with low levels of proliferating T cells within the less differentiated T-cell subpopulations (defined by CD45RA, CCR7, CD27, CD28). Despite a prior history of progressive disease, PCAT patients exhibited many of the immunologic characteristics of LTNP, including high but variable frequencies of IL2⁺, IFN-γ⁺ CD4⁺ T cells (p < 0.001 for PCAT vs progressors) and high levels of IFN-bright CD4⁺ T cells (p = 0.03). Measures of immune activation were lower in all T-cell memory subsets (defined by CD45RA and CD27) in LTNP and PCAT than in progressors. 

Conclusion:  Control of HIV replication is most strongly correlated with high levels HIV-specific IL-2⁺ CD4⁺ T cells and IFN-γ bright T cells, and low levels of T-cell activation. This immunologic state can be best characterized as one in which the host responds to HIV by expanding but not exhausting HIV-specific memory T cells while maintaining a relatively quiescent immune system. Despite a history of advanced HIV disease, a subset of individuals with multi-drug resistant HIV exhibit an immunologic profile comparable to that in LTNP, suggesting that functional immunity can be reconstituted with partially suppressive HAART.

Keywords: HIV specific immunity; T cell activation; drug resistance