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Abstract
Inhibition of HIV-1 replication by caffeine and caffeine-related methylxanthines
Nunnari G.1, Argyris E.1, Fang J.1, Mehlman K.1, Pomerantz R.1, Daniel R.1
1Thomas Jefferson University, Philadelphia, United States of America
Introduction: Human immunodeficiency virus type I (HIV-1) DNA integration is an essential step of viral replication. We have suggested recently that this stage of HIV-1 life-cycle triggers a cellular DNA damage response and requires cellular DNA repair proteins for its completion. These include DNA-PK, ATR and, at least in some circumstances, ATM. Host cell proteins may constitute an attractive target for anti-HIV-1 therapeutics, since development of drug resistance against compounds targeting these cellular cofactor proteins is unlikely.
Methods: Human peripheral blood mononuclear cells (PBMCs) were infected with two HIV-1 strains, NL4-3 and ADA. Simultaneously, PBMCs were treated with caffeine and caffeine-related methylxanthines. HIV-1 growth was evaluated by p24 antigen assay. Standard methods, including quantitative PCR and Alu-PCR, were used to determine the effect of caffeine and other compounds on individual steps of the HIV-1 life-cycle.
Results: In this study, we show that an inhibitor of ATR and ATM kinases, caffeine, can suppress replication of infectious HIV-1 strains, and provide evidence that caffeine exerts its inhibitory effect at the integration step of the HIV-1 life-cycle. We also demonstrate that caffeine-related methylxanthines including the clinically used compound, theophylline, act at the same step of the HIV-1 life-cycle as caffeine and efficiently inhibit HIV-1 replication in primary human cells.
Conclusions: These data reveal the feasibility of therapeutic approaches targeting host cell proteins and further support the hypothesis that ATR and ATM proteins are involved in retroviral DNA integration.
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