Hiding in plain sight - platelets, the silent carriers of HIV-1

Abstract

There are approximately 38 million people globally living with Human immunodeficiency virus 1 (HIV-1) and given the tremendous success of combination antiretroviral therapy (cART) this has dramatically reduced mortality and morbidity with prevention benefits. However, HIV-1 persists during cART within the human body and re-appears upon cART interruption. This HIV-1 reservoir remains a barrier to cure with cellular sites of viral persistence not fully understood. In this study we provide evidence corroborating a recently published article in STM demonstrating the role of platelets as a novel cellular disseminator of HIV-1 particles in the setting of viral suppression. Using classical transmission electron microscopy with and without immunogold labeling, we visualize HIV-1 in both platelets and monocytes in cART suppressed HIV donors. Our study suggests that due to the close proximity of platelets and monocytes an alternative life cycle of HIV-1 cycling within monocytes and platelets without the need of active replication under cART occurs. Our findings are supported by the lack of detectable HIV-1 particles in platelets derived from HIV uninfected donors or the 'Berlin' patient suggesting that platelets may serve as an underappreciated hidden bearer for HIV-1 and should be considered in HIV remission studies and trials.

Keywords: HIV-1; HIV-1 persistence; HIV-1 reservoir; monocytes; platelets.

Figure 1:. Hiding in plain sight – Platelets as carriers of HIV-1.

Platelets (P) adhering to monocytes (M) and macrophages (Mc) from healthy (HIV^neg), suppressed HIV-1-infected individuals (HIV^pos), and the ‘Berlin’ patient by SEM (A). TEM sections imaging monocyte preparations and platelets surrounding monocytes (B); platelet histological features: glycogen pockets (g), open canalicular system (OCS), and electron dense granules (DG). Viral particles (arrows) are detectable in platelets of HIV^pos. Pseudopods on platelets (arrowheads) were apparent, indicative of an increased activated state. Virus-like particles detected on surface by SEM of HIV^pos monocytes treated with HDAC inhibitors (inh) (C) and intracellularly as detected by TEM (D). (E) Quantification of platelets with visual VLPs from TEM images of monocyte/platelet preparations with control or HDAC inhibitor treatment. Platelets with VLP were counted and separated into two groups; platelets with 1–2 VLPs or with >2 VLPs. (F)Visualization of VLPs in supernatant (SN) of HDAC inh. treated monocyte/platelet preparations. (G) TEM imaging reveals signs of monocytes phagocytosing platelets. (H) p24 immunogold labeling of monocyte/platelet preparations. Positive p24 staining is indicated by arrows.

Figure 2:. Hiding in plain sight – Platelets as carriers of HIV-1.

Proposed ‘life cycle’ of HIV-1 utilizing platelets as a carrier: Upon HIV-1 infection of a human body several cell types will be infected with HIV-1. HIV-1 integrates rather rapidly in the DNA of various cell types including megakaryocytes and monocytes. Additionally, in the scenario of untreated HIV-1 infection platelets can engulf HIV-1 particles. Due to the close contact of platelets and monocytes HIV-1 transfer between these two cell types, especially upon phagocytosis of dying platelets will occur. Upon start of cART treatment no active HIV-1 replication can occur, however, few platelets will still harbor HVI-1 particles and allow for an alternative ‘life’ cycle of HIV-1 under cART therapy allowing for circulation of active HIV-1 particles within monocytes, which subsequently can enter tissues, differentiate into macrophages carrying HIV-1 particles. It is likely that upon cell death within the tissue HIV-1 can either be distributed within the tissue or phagocytosed by other cell types entering another life cycle without the need of active replication, allowing HIV-1 lingering within cells and tissues able to infect various cell types.