Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS

Abstract

The restoration of the immune system prompted by antiretroviral therapy (ART) has allowed drastically reducing the mortality and morbidity of HIV infection. However, one main source of clinical concern is the persistence of immune hyperactivation in individuals under ART. Chronically enhanced levels of T-cell activation are associated with several deleterious effects which lead to faster disease progression and slower CD4(+) T-cell recovery during ART. In this article, we discuss the rationale, and review the results, of the use of antimalarial quinolines, such as chloroquine and its derivative hydroxychloroquine, to counteract immune activation in HIV infection. Despite the promising results of several pilot trials, the most recent clinical data indicate that antimalarial quinolines are unlikely to exert a marked beneficial effect on immune activation. Alternative approaches will likely be required to reproducibly decrease immune activation in the setting of HIV infection. If the quinoline-based strategies should nevertheless be pursued in future studies, particular care must be devoted to the dosage selection, in order to maximize the chances to obtain effective in vivo drug concentrations.

Figure 1

Mechanistic model of HIV-induced persistent immune-activation. a HIV enters CD4-expressing plasmacytoid dendritic cells (pDCs); b the virus is endocytosed, decapsided and its RNA is recognized by toll-like receptor 7 (TLR-7); c stimulation of TLR-7 prompts a signaling cascade inducing IFN-α transcription in the nucleus; d production of IFN-α favors activation of several cell subsets such as T, B and natural killer (NK) lymphocytes. Chloroquine (CQ) is postulated to reduce the efficiency of this mechanism by accumulating in endosomes and decreasing HIV-mediated TLR-7 signaling [44].

Figure 2

Comparison of the susceptibility to chloroquine/hydroxychloroquine and auranofin of the cellular subsets involved in HIV production and persistence. Shown in the figure is a schematic depiction of a activation and b differentiation stages of CD4⁺ T-lymphocytes and their correlation with viral production, latency and viral reactivation. Both chloroquine/hydroxychloroquine and auranofin can influence these transitions by exerting a pro-apoptotic effect, the efficacy of which is graphically exemplified by the intensity of the blue color in the corresponding rectangles. Efficacy gradients are based on data derived from Refs. [45, 48, 50].

Figure 3

Published clinical studies evaluating the effects of chloroquine/hydroxychloroquine administration, alone or in combination with other drugs, in HIV infected subjects. Highlighted in blue, red or white are the studies that have reported a positive, negative, or neutral outcome of the therapy respectively. CQ chloroquine, HCQ hydroxychloroquine.