Abstract
Persistence of latent HIV-1 in macrophages (MACs) and T-helper lymphocytes (THLs) remain a major therapeutic challenge. Currently available latency reversing agents (LRAs) are not very effective in vivo. Therefore, understanding of physiologic mechanisms that dictate HIV-1 latency/reactivation in reservoirs is clearly needed. Mesenchymal stromal/stem cells (MSCs) regulate the function of immune cells; however, their role in regulating virus production from latently-infected MACs & THLs is not known. We documented that exposure to MSCs or their conditioned media (MSC-CM) rapidly increased HIV-1 p24 production from the latently-infected U1 (MAC) & ACH2 (THL) cell lines. Exposure to MSCs also increased HIV-1 long terminal repeat (LTR) directed gene expression in the MAC and THL reporter lines, U937-VRX and J-Lat (9.2), respectively. MSCs exposed to CM from U1 cells (U1-CM) showed enhanced migratory ability towards latently-infected cells and retained their latency-reactivation potential. Molecular studies showed that MSC-mediated latency-reactivation was dependent upon both the phosphatidyl inositol-3-kinase (PI3K) and nuclear factor-κB (NFκB) signaling pathways. The pre-clinically tested inhibitors of PI3K (PX-866) and NFκB (CDDO-Me) suppressed MSC-mediated HIV-1 reactivation. Furthermore, coexposure to MSC-CM enhanced the latency-reactivation efficacy of the approved LRAs, vorinostat and panobinostat. Our findings on MSC-mediated latency-reactivation may provide novel strategies against persistent HIV-1 reservoirs.
Highlights
The epidemic of acquired immune deficiency syndrome (AIDS) has become an adversary of alarming proportions, with more than 39 million deaths worldwide[1,2]
We compared the effect of adipose-derived mesenchymal stem/stromal cells (MSCs) (ASCs) and differentiated adipocytes (ADs) on virus production from latently-infected U1 monocytic cells, by measuring human immunodeficiency virus type-1 (HIV-1) p24 levels in culture supernatants (Fig. 1)
We compared the effect of exposure to phorbol 12-myristate 13-acetate (PMA) (10 ng/mL) and/or ASC-conditioned medium (CM) (10% and 25%) on HIV-1 reactivation from U1 cells (Fig. 1C)
Summary
The epidemic of acquired immune deficiency syndrome (AIDS) has become an adversary of alarming proportions, with more than 39 million deaths worldwide[1,2]. The advent of highly active antiretroviral therapy (HAART) has been very effective in suppressing plasma viral load (PVL)[3], HIV-1 persistence in latent tissue reservoirs remains a significant challenge to long-term cure[4,5]. HIV-1 preferentially infects cells of the lymphoid and myeloid lineages, e.g. T-helper lymphocytes (THLs) and monocytes-derived macrophages (MACs), where the virus integrates into host cell chromosome to form the provirus[11] Transcriptional activation of this latent provirus is primarily regulated by both viral proteins (e.g. Tat and Nef) and host-cell transcription factors (e.g. NFκB and NFAT) that recognize specific sequences within the HIV-1 long terminal repeat (LTR). Our findings on MSC-mediated reactivation of latent HIV-1 may provide novel strategies to eliminate the persistent viral reservoirs in patients
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