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Journal of Virology, May 2005, p. 5625-5631, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5625-5631.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Macrophage Inflammatory Protein 1{alpha} Inhibits Postentry Steps of Human Immunodeficiency Virus Type 1 Infection via Suppression of Intracellular Cyclic AMP

Carol-Ann Amella,1 Barbara Sherry,1 David H. Shepp,2,{dagger} and Helena Schmidtmayerova1*

Institute for Medical Research at North Shore-LIJ, Center for Immunology and Inflammation, 350 Community Drive, Manhasset, New York 11030,1 North Shore University Hospital, Division of Infectious Disease, 300 Community Drive, Manhasset, New York 110302

Received 23 August 2004/ Accepted 10 December 2004

Primary isolates of human immunodeficiency virus type 1 (HIV-1) predominantly use chemokine receptor CCR5 to enter target cells. The natural ligands of CCR5, the ß-chemokines macrophage inflammatory protein 1{alpha} (MIP-1{alpha}), MIP-1ß, and RANTES, interfere with HIV-1 binding to CCR5 receptors and decrease the amount of virions entering cells. Although the inhibition of HIV-1 entry by ß-chemokines is well documented, their effects on postentry steps of the viral life cycle and on host cell components that control the outcome of infection after viral entry are not well defined. Here, we show that all three ß-chemokines, and MIP-1{alpha} in particular, inhibit postentry steps of the HIV-1 life cycle in primary lymphocytes, presumably via suppression of intracellular levels of cyclic AMP (cAMP). Productive HIV-1 infection of primary lymphocytes requires cellular activation. Cell activation increases intracellular cAMP, which is required for efficient synthesis of proviral DNA during early steps of viral infection. Binding of MIP-1{alpha} to cognate receptors decreases activation-induced intracellular cAMP levels through the activation of inhibitory G proteins. Furthermore, inhibition of one of the downstream targets of cAMP, cAMP-dependent PKA, significantly inhibits synthesis of HIV-1-specific DNA without affecting virus entry. These data reveal that ß-chemokine-mediated inhibition of virus replication in primary lymphocytes combines inhibitory effects at the entry and postentry levels and imply the involvement of ß-chemokine-induced signaling in postentry inhibition of HIV-1 infection.

* Corresponding author. Mailing address: Institute for Medical Research at North Shore-LIJ, 350 Community Drive, Manhasset, NY 11030. Phone: (516) 562-9506. Fax: (516) 365-5090. E-mail: HSchmidt{at}nshs.edu.

{dagger} Present address: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404.

Journal of Virology, May 2005, p. 5625-5631, Vol. 79, No. 9
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.9.5625-5631.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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