The Nucleoside Triphosphate Diphosphohydrolase-1/CD39 Is Incorporated into Human Immunodeficiency Type 1 Particles, Where It Remains Biologically Active

Abstract

Human immunodeficiency virus type 1 (HIV-1) carries a variety of host proteins in addition to virus-encoded structural proteins, both in its envelope and inside the viral particle. Previous studies have reported that the HIV-1 life-cycle is affected by such virus-associated host cell surface proteins. The nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), also known as CD39, is a plasma membrane-bound ectoenzyme that hydrolyzes extracellular ATP and ADP to AMP. It has been shown that CD39 inhibits platelet function, and is thus a critical thromboregulatory molecule. We demonstrate here that host-derived CD39 is acquired by both laboratory-adapted and clinical variants of HIV-1 produced in cellular reservoirs of the virus. Moreover, purified CD39-bearing virions, but not isogenic viruses lacking CD39, display strong ATPase and ADPase activities. It is of particular interest that virions bearing this cellular enzyme can inhibit ADP-induced platelet aggregation, an effect blocked by an NTPDase inhibitor. On the basis of published and the present data on the functionality of human cellular proteins embedded within HIV-1, it can be proposed that these proteins might contribute to some of the immunologic deficiencies seen in infected individuals.

Comprehensive Analysis of Frequency and Phenotype of T Regulatory Cells in HIV Infection: CD39 Expression of FoxP3+T Regulatory Cells Correlates with Progressive Disease

“…While the expression of CD39 could be seen as a mere surrogate marker for immune activation in these individuals (11,47), recent studies suggest a functional role for CD39 in pathogenesis (3,8,30,40). CD39 functions as a nucleoside triphosphate diphsphohydrolase 1 (NTPDase 1), which converts ATP (a proinflammatory stimulus) into AMP, and also boosts the production of adenosine (8), thereby dampening the general immune activation (4,16).…”

Possible Effects of Microbial Ecto-Nucleoside Triphosphate Diphosphohydrolases on Host-Pathogen Interactions

“…In addition, it now appears that CD39 is incorporated into HIV virions, where it remains enzymatically active (9). The CD39-bearing virions can inhibit platelet aggregation, although the importance of this in pathogenesis is unclear, as severe bleeding is not common in HIV/AIDS patients (9). Enhanced CD39 expression may alternatively have effects on extracellular ATP concentrations and purinergic signaling, in a manner similar to that for other pathogens bearing surfacelocated NTPDases, although this remains to be proven.…”

Crystallographic Evidence for a Domain Motion in Rat Nucleoside Triphosphate Diphosphohydrolase (NTPDase) 1

“…[14][15][16] In tandem with the ecto-5′-nucleotidase CD73, this generates adenosine, a known immunosuppressive substance. [17][18][19] Recent studies show that CD39 is involved in the progression of AIDS [20][21][22] and is required for the pathological angiogenesis and progression of tumors. [23][24][25][26][27][28][29] This intense and multifunctional physiological integration of NTPDase1 has led to its identification both as a drug target and as a drug itself.…”