Assessment of chloroquine as a modulator of immune activation to improve CD4 recovery in immune nonresponding HIV‐infected patients receiving antiretroviral therapy

Abstract

ObjectivesChloroquine (CQ), an anti-inflammatory drug, inhibits Toll-like receptor (TLR) signalling in plasmacytoid dendritic cells (pDCs) and may be beneficial for HIV-infected patients in whom immune activation persists despite effective antiretroviral therapy (ART). The effect of CQ on CD4 T-cell recovery and immune activation in immune nonresponding patients receiving successful ART was therefore studied. MethodsNineteen adults on ART with CD4 counts ≤350 cells/μL and undetectable viral load (VL) orally received CQ at 250 mg/day for 24 weeks. Side effects, CD4 and CD8 T-cell counts, VL, T-cell activation, pDC proportion and plasma inflammatory markers were assessed at baseline, at 24 weeks, and at 12 weeks after CQ discontinuation (clinicaltrial.org registration #NCT02004314). ResultsCQ was well tolerated and all patients maintained an undetectable VL. The absolute CD4 and CD8 T-cell counts and their percentages, the pDC proportion, T-cell activation, D-dimer and C-reactive protein (CRP) plasma levels and the kynurenine/tryptophan ratio did not change with CQ treatment. Among nine cytokines/chemokines measured, only levels of interferon (IFN)-α2 were significantly increased by CQ treatment. ConclusionsCQ was well tolerated in patients with low CD4 T-cell counts despite long-term effective ART; however, 24 weeks of CQ treatment did not improved CD4 T-cell recovery, lymphoid and myeloid immune activation or inflammatory markers.Keywords: antiretroviral therapy, CD4 T-cell recovery, chloroquine, HIV, Toll-like receptors. Accepted 9 April 2014 IntroductionThe chronic phase of HIV infection is characterized by the progressive depletion of CD4 T cells as well as persistent immune activation [1][2][3]. Antiretroviral treatment (ART) suppresses viral replication and leads to recovery of CD4 T cells in most individuals. However, up to 30% of HIVinfected patients who are receiving long-term ART show a suboptimal CD4 T-cell recovery despite achieving complete suppression of the plasma viral load (VL) [4]. In patients receiving effective ART, the persistence of enhanced T-cell activation [defined by CD38 and human leucocyte antigen [5][6][7][8][9]. The persistence of immune activation and inflammation in treated patients can be related to HIV persistence and/or low levels of viral replication directly, or indirectly through lymph node fibrosis and enhanced translocation of microbial origin products from the gastrointestinal tract to blood [2,3,6]. Microbial products from the gut released into systemic circulation trigger Toll-like receptor (TLR) pathways in monocytes and dendritic cells (DCs), resulting in enhanced immune activation [6,10]. Therefore, supplementary therapeutic strategies targeting immune activation or inflammation should contribute to improving CD4 T-cell recovery. Therapies targeting TLR activation represent an attractive strategy. Chloroquine (CQ), a quinolone antimalarial drug, has been used for several decades as an antimalarial agent and recently to treat immune-mediated inflammatory disorders suc...

Inflammation, immune activation, and cardiovascular disease in HIV

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Immunosenescence and hurdles in the clinical management of older HIV-patients

“…In some studies this molecule was shown to reduce immune activation markers (i.e., IL-6, TNF-a and LPS) and CD8 T-cells expressing CD38CHLA-DRC and Ki-67, 158-161 while other researchers found no effect on immune-activation. [162][163][164] A possible target is also represented by TNF itself, which may be antagonized by several molecules currently in use for rheumatologic diseases. A study in rhesus macaques showed that adalimumab, a human anti-TNF monoclonal antibody, was able to reduce infiltration of polymorphonuclear cells into the T-cell zone of lymphoid tissues, diminishing also lymphoid tissue fibrosis; nevertheless, no effect on plasma immune activation was proven.…”

Divergent Expression of CXCR5 and CCR5 on CD4+ T Cells and the Paradoxical Accumulation of T Follicular Helper Cells during HIV Infection

“…Another open question is why it is that strategies to reduce T cell activation offer little or no benefit as adjuncts to ART, e.g., cyclosporine A (99), corticosteroids (100), mycophenylate motefil (101), chloroquine (102), or even recombinant IL-2 (103), which is known to antagonize the generation of Tfh (104). …”