Human immunodeficiency virus type I (HIV-1) DNA integration is an essential step of viral replication. We have suggested recently thatthis stage of HIV-1 life-cycle triggers a cellular DNA damage response and requires cellular DNA repair proteins for its completion. Theseinclude DNA-PK (DNA-dependent protein kinase), ATR (ataxia telangiectasia and Rad3-related), and, at least in some circumstances, ATM(ataxia telangiectasia mutated). Host cell proteins may constitute an attractive target for anti-HIV-1 therapeutics, since development of drugresistance against compounds targeting these cellular cofactor proteins is unlikely. In this study, we show that an inhibitor of ATR and ATMkinases, caffeine, can suppress replication of infectious HIV-1 strains, and provide evidence that caffeine exerts its inhibitory effect at theintegration 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. Thesedata reveal the feasibility of therapeutic approaches targeting host cell proteins and further support the hypothesis that ATR and ATM proteinsare involved in retroviral DNA integration.
Inhibition of HIV-1 replication by caffeine and caffeine-related methylxanthines
NUNNARI G;
2005-01-01
Abstract
Human immunodeficiency virus type I (HIV-1) DNA integration is an essential step of viral replication. We have suggested recently thatthis stage of HIV-1 life-cycle triggers a cellular DNA damage response and requires cellular DNA repair proteins for its completion. Theseinclude DNA-PK (DNA-dependent protein kinase), ATR (ataxia telangiectasia and Rad3-related), and, at least in some circumstances, ATM(ataxia telangiectasia mutated). Host cell proteins may constitute an attractive target for anti-HIV-1 therapeutics, since development of drugresistance against compounds targeting these cellular cofactor proteins is unlikely. In this study, we show that an inhibitor of ATR and ATMkinases, caffeine, can suppress replication of infectious HIV-1 strains, and provide evidence that caffeine exerts its inhibitory effect at theintegration 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. Thesedata reveal the feasibility of therapeutic approaches targeting host cell proteins and further support the hypothesis that ATR and ATM proteinsare involved in retroviral DNA integration.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
