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Blood, 15 November 2006, Vol. 108, No. 10, pp. 3305-3312.
Prepublished online as a Blood First Edition Paper on July 20, 2006; DOI 10.1182/blood-2006-04-014829.
 Previous Article | Next Article 
Submitted April 6, 2006
Accepted June 29, 2006
Lentivirus vectors expressing short hairpin RNAs against the U3-overlapping region of HIV nef inhibit HIV replication and infectivity in primary macrophages
Takuya Yamamoto, Hiroyuki Miyoshi, Norio Yamamoto, Naoki Yamamoto, Jun-ichiro Inoue, and Yasuko Tsunetsugu-Yokota*
National Institute of Infectious Diseases; The University of Tokyo, Tokyo, Japan
Subteam for Manipulation of Cell Fate, BioResource Center, RIKEN Tsukuba Institute, Tsukuba, Japan
Department of Molecular Virology, Bio-Response, Tokyo Medical and Dental University, Tokyo, Japan
Tokyo Medical and Dental University; National Institute of Infectious Diseases, Tokyo, Japan
Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Japan
Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan
* Corresponding author; email: yyokota{at}nih.go.jp.
Although successful attempts to inhibit HIV-1 replication in T-cells using RNAi have been reported, the effect of HIV-specific RNAi on macrophages is not well known. Macrophages are key targets for anti-HIV-1 therapy, because they are able to survive long after the initial infection with HIV, and can spread the virus to T-cells. In this study, we identified a putative RNAi target of HIV, consisting of the portion of the nef gene overlapping the U3 region (Nef366), and generated a lentivirus-based short hairpin RNA (shRNA) expression vector (Lenti shNef366). We showed here that Lenti shNef366 inhibits 1) HIV-1 replication in a monocytic cell line and in primary monocyte-derived macrophages (MDMs), 2) reactivation of latent HIV-1 infection, and 3) the production of secondary HIV-1 from MDMs harboring a genomic copy of Nef366. Moreover, we found that the upregulated production of macrophage inflammatory protein-1 (MIP-1), but not MIP-1 , in MDMs by Nef expression was considerably suppressed by Lenti shNef366, which suggests that HIV-1 dissemination to T-cells through its interaction with HIV-1 infected MDMs can also be controlled by Lenti shNef366. Thus, lentivirus-mediated shRNA expression targeting the U3-overlapping region of HIV nef represents a feasible approach to genetic vaccine therapy for HIV-1.
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