Dendritic Cell-induced Activation of Latent HIV-1 Provirus in Actively Proliferating Primary T Lymphocytes

Abstract

HIV-1 latency remains a formidable barrier towards virus eradication as therapeutic attempts to purge these reservoirs are so far unsuccessful. The pool of transcriptionally silent proviruses is established early in infection and persists for a lifetime, even when viral loads are suppressed below detection levels using anti-retroviral therapy. Upon therapy interruption the reservoir can re-establish systemic infection. Different cellular reservoirs that harbor latent provirus have been described. In this study we demonstrate that HIV-1 can also establish a silent integration in actively proliferating primary T lymphocytes. Co-culturing of these proliferating T lymphocytes with dendritic cells (DCs) activated the provirus from latency. Activation did not involve DC-mediated C-type lectin DC-SIGN signaling or TCR-stimulation but was mediated by DC-secreted component(s) and cell-cell interaction between DC and T lymphocyte that could be inhibited by blocking ICAM-1 dependent adhesion. These results imply that circulating DCs could purge HIV-1 from latency and re-initiate virus replication. Moreover, our data show that viral latency can be established early after infection and supports the idea that actively proliferating T lymphocytes with an effector phenotype contribute to the latent viral reservoir. Unraveling this physiologically relevant purging mechanism could provide useful information for the development of new therapeutic strategies that aim at the eradication of HIV-1 reservoirs.

Promising Role of Toll-Like Receptor 8 Agonist in Concert with Prostratin for Activation of Silent HIV

“…However, increasing concentrations of ICOSL-blocking antibodies did not reverse latency (data not shown), despite ICOSL expression by MDDCs (110). Of note, ICAM1, upregulated by TNF signaling on DCs, was recently associated with HIV reactivation in proliferating CD4 ϩ T cells, in a similar system (111). Since Jurkat cells do not multimerize LFA-1, which is crucial for its activation and interaction with ICAM1, we did not challenge this axis (112).…”

Gp120 binding with DC-SIGN induces reactivation of HIV-1 provirus via the NF-κB signaling pathway

“…Myeloid cells, such as DC, are non-permissive for HIV-1, and the rate of infection is very low [22]. Studies of HIV-1 latency in DC are hindered by the difficulties associated with effectively developing replicative infection in DC, and the absence of models or cell lines for DC reservoirs [23]. To investigate the role of DC-SIGN-induced signaling pathways in HIV-1 provirus reactivation, we generated cell models of HIV-1 DC reservoirs using 293T cells transfected with a DC-SIGN expression plasmid and HIV-1 5′LTR reporters and CEMBru cells transfected with a DC-SIGN expression plasmid.…”

Plasmodium infection reduces the volume of the viral reservoir in SIV-infected rhesus macaques receiving antiretroviral therapy

“…The higher levels of IFN-γ activity (represented by higher levels of plasma neopterin) induced by malaria also indicated immune system and T cell activation [13]. The higher levels of neopterin induced by malaria especially indicated the activation of macrophages [36], which may be more critical in the process of SIV reservoir purging because Van der Sluis et al have shown that APCs such as myeloid dendritic cells can activate latent T cells more than other T cell activators do [37]. A correlation analysis of plasma neopterin and the activation level of CD4+ T cells might also have uncovered this phenomenon (Additional file 2: Figure S2D).…”