Abstract/Details

Purinergic receptors are required for HIV-1 infection of primary human macrophages


2011 2011

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Abstract (summary)

Macrophages are critical mediators of disease throughout the course of HIV infection. They are one of the first cells to become infected and they act as significant viral reservoirs. HIV enters macrophages through binding to CD4 and CCR5 and the subsequent fusion events that occur are generally believed to be virus driven. However, evidence suggests that signaling through CCR5 and increases in intracellular calcium may facilitate HIV entry. Purinergic receptors, P2X and P2Y, are important mediators of the inflammatory response to pathogens and other causes of cellular damage. We hypothesize that HIV's binding to macrophages results in ATP release and autocrine activation of purinergic receptors, leading to increased intracellular calcium, which facilitates HIV replication. We examined HIV replication in primary human macrophages in the presence of oxidized ATP (oATP), a P2X receptor antagonist, and suramin, a P2X and P2Y antagonist. We found that both inhibitors significantly block viral replication by greater than 85%. Inhibition of replication by oATP is dose-dependent and results in a decrease in the percentage of cells infected. Using a viral entry assay, we also demonstrated that oATP inhibits HIV entry into macrophages. To determine what purinergic receptors are involved in viral replication, we used the more specific inhibitors NF 279 (P2X1), A-740003 (P2X7), and MRS 2179 (P2Y1). All three antagonists significantly inhibited viral replication in a dose-dependent manner. Interestingly, only NF 279 inhibited viral entry, indicating that P2X1 may be the predominant receptor mediating viral entry, while the other receptors participate in later stages of HIV replication. To determine how HIV's binding results in purinergic receptor activation, we examined ATP release following treatment with the HIV surface protein gp120. We found that gp120 induces a significant increase in ATP release from macrophages within the first 15 minutes of treatment. Our results identify a novel family of host proteins that participate in HIV replication, the P2 receptors, which may represent an appropriate target for therapeutic intervention.

Indexing (details)


Subject
Cellular biology;
Virology;
Immunology
Classification
0379: Cellular biology
0720: Virology
0982: Immunology
Identifier / keyword
Health and environmental sciences; Biological sciences; AIDS; ATP; HIV-1 infection; Macrophages; Purinergic receptors
Title
Purinergic receptors are required for HIV-1 infection of primary human macrophages
Author
Hazleton, Joy Elaine
Number of pages
243
Publication year
2011
Degree date
2011
School code
0266
Source
DAI-B 72/08, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781124652894
Advisor
Berman, Joan W.
University/institution
Yeshiva University
University location
United States -- New York
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3456019
ProQuest document ID
871500095
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/871500095
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