Platelets in HIV: A Guardian of Host Defence or Transient Reservoir of the Virus?

Abstract

The immune and inflammatory responses of platelets to human immunodeficiency virus 1 (HIV-1) and its envelope proteins are of great significance to both the treatment of the infection, and to the comorbidities related to systemic inflammation. Platelets can interact with the HIV-1 virus itself, or with viral membrane proteins, or with dysregulated inflammatory molecules in circulation, ensuing from HIV-1 infection. Platelets can facilitate the inhibition of HIV-1 infection via endogenously-produced inhibitors of HIV-1 replication, or the virus can temporarily hide from the immune system inside platelets, whereby platelets act as HIV-1 reservoirs. Platelets are therefore both guardians of the host defence system, and transient reservoirs of the virus. Such reservoirs may be of particular significance during combination antiretroviral therapy (cART) interruption, as it may drive viral persistence, and result in significant implications for treatment. Both HIV-1 envelope proteins and circulating inflammatory molecules can also initiate platelet complex formation with immune cells and erythrocytes. Complex formation cause platelet hypercoagulation and may lead to an increased thrombotic risk. Ultimately, HIV-1 infection can initiate platelet depletion and thrombocytopenia. Because of their relatively short lifespan, platelets are important signalling entities, and could be targeted more directly during HIV-1 infection and cART.

Keywords: HIV-1; platelet; platelet complexes; receptors; thrombotic risk.

Figure 1

A generic illustration of the initial attachment of HIV-1 to a CD4⁺ cell, resulting in in a series of sequential steps that allows viral replication. Initial HIV-1 cell contact result in the interaction of viral envelope glycoprotein gp120 with CD4 receptors, to form a (1) gp120/CD4 complex on the host cell surface (4). This interaction induces a conformational change in the envelope protein that exposes a chemokine receptor binding site. (2 and 3) Association of gp120 with chemokine receptor CC chemokine receptor 5 (CCR5) or chemokine receptor 4 (CXCR4), promotes a rearrangement of the transmembrane envelope protein gp41, resulting in the (4) fusion of the viral and cellular membranes and the entry of the viral capsid into the cell (–6). CXCR4 and CCR5 were initially identified for their role in HIV-1 entry of CD4⁺ T cells through its interaction with gp120 (7). CCR5 is a G protein-coupled receptor (8), with seven transmembrane segments and an eighth α-helix parallel to the plasma membrane (6). (5) Viral RNA is now released into the cell, followed by (6) reverse transcriptase to HIV-1 DNA; (7) integration and transcription in the nucleus; (8) translation and assembly in the cell cytoplasm; followed by (9) budding and release and maturation. Diagram created with BioRender (https://biorender.com/).

Figure 2

Scanning electron microscopy micrograph plate from patients with HIV and with deep vein thrombosis and on primary treatment (emtricitabine, tenofovir and efavirenz) (cART). (A) Hyperactivated platelets with pseudopodia, spreading and microparticle formation (white arrow). (B) Platelet-erythrocyte complex, yellow arrow: platelet forming pseudopodia that attaches to an erythrocyte membrane (raw data taken from (42).

Figure 3

HIV-1 interact with platelets, resulting in (hyper)activation and microparticle formation. Platelet receptors that are known to bind viruses (16): C-C chemokine receptor type 1, 2 and 4 (CXCR1, CXCR2, CXCR4), as well as C-C chemokine receptor type 1, 3 and 4 (CCR1, CCR3 and CCR4). Diagram created with BioRender (https://biorender.com/).

Figure 4

(1) After virus endocytosis, platelets express P-selectin on their membranes, followed by platelet-T cell complex formation (2); P-selectin on platelet membranes are also recognized by macrophages, possibly by the Fcγ-receptor; clearance may result due to either receptor binding or phagocytosis (3). CD40L is released from platelets and can migrate to membranes or shed as soluble (s)CD40L (4). sCD40L can bind to both the α_IIbβ₃ or CD40 receptors (5) The P-selectin on the membranes of sCD40L-activated platelets can also form complexes with monocytes (6). Platelet-neutrophils also form complexes (7) Diagram created with BioRender (https://biorender.com/).

Figure 5

HIV-1 and its trans activating factor (Tat) particles interacting with platelets and endothelial cells. Atherosclerotic plaque formation is known to cause endothelial damage and shown here to indicate an area of endothelial damage. Tat is expressed by HIV-1 infected cells and activates platelets through chemokine receptor CCR3 and integrin β3 (86) (1). Tat binds to endothelial cell integrin receptor α_vβ₃ (2). gp120 binds to endothelial cell receptors CXCR4 and CCR5 (3). Diagram created with BioRender (https://biorender.com/). Cells are not drawn to scale.