We measured both CD4 and CD8 T-cell responses to Gag, Pol, Env, and Nef HIV antigens, by using overlapping peptide pools for HIV clade B viruses. In all cases, we found no significant changes in any TNF-, IFN-γ-, or IL-2-producing HIV- or cytomegalovirus (CMV)-specific CD8 or CD4 T cells during the complete course of CQ treatment or in the placebo control group (data not shown).
In summary, we found that administration of CQ during chronic HIV infection resulted in decreased immune activation as measured by a parameter closely correlated with disease progression, the percentage of CD38+ HLA-DR+ CD8 memory T cells. In addition, Ki-67 expression was reduced in both CD4 and CD8 memory T-cell populations during the first phase of CQ treatment. While our study was limited by the small number of placebo controls, we have extended previous studies of CQ therapy to show decreases in T-cell immune activation with CQ treatment.
CD8 T cells are increased in frequency during chronic viral infections (2
) and on stimulation with TLR3 and TLR9 ligands (7
). CQ is an inhibitor of signaling by the endosomal TLRs, TLR3, TLR7, TLR8, and TLR9 (11
). Thus, it is plausible that suppression of intracellular TLR signaling resulted in the decrease in CD38+
CD8 T cells with CQ treatment in these HIV-infected subjects. This could occur by suppression of intracellular TLR signaling in monocytes and dendritic cells (DCs) which, in turn, results in the reduction in CD38+
CD8 T cells, as previously shown to occur with DC-T-cell cocultures with CQ in vitro
). It is unclear why the decrease in CD38 and HLA-DR expression was sustained during the complete course of CQ treatment, whereas Ki-67 and LPS levels were decreased only after the first month of treatment. However, the latter two parameters followed similar patterns of suppression and, therefore, may be more directly causally related.
We have identified parameters of immune activation that are altered by CQ alone, in the absence of ART. It is possible that differences in CQ dosage and regimen and the limited statistical power of our study account for why we did not observe decreases in viral load as reported in other studies. Since our study, another report showed that a daily dosage of 250 mg CQ, as was given to the majority of the participants in our study, was not sufficient to decrease viral load (20
). The effects of CQ in combination therapy studies have been reported to be qualitatively different than the antiretroviral effects and not simply additive (15
). Taken together, our results suggest that CQ intervention suppresses key aspects of HIV disease pathogenesis that are correlated with disease progression.