Identification of novel therapeutic targets for HIV infection through functional genomic cDNA screening.
Despite decades of research, HIV remains a global health threat. Issues of multi-drug resistance and lack of an effective vaccine have recently led to the targeting of host factors for anti-viral drug development. While a few genome-wide screens for novel HIV co-factors have been reported, the promise of finding a therapeutic target has yet to be realized. Here, we report a screen of a cDNA library representing 15,000 unique genes in an infectious HIV system, and show that genomic screening can lead to the identification of novel proviral host factors. Mixed lineage kinase 3 (MLK3/MAP3K11) was identified as one of the strongest enhancers of infection and mutant studies show that its activity is dependent on its kinase function. Consistent with its known role in the activation of the AP-1 pathway through JNK kinase, MLK3 was able to enhance Tat-dependent HIV transcription in vitro thus leading to an increase in infection signal. RNA interference studies confirm the involvement of endogenous MLK3 in HIV infection, further implicating this kinase as a potential therapeutic target.
Nguyen
Deborah G
DG
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA. deborah.nguyen@gnf.org
Yin
Hong
H
Zhou
Yingyao
Y
Wolff
Karen C
KC
Kuhen
Kelli L
KL
Caldwell
Jeremy S
JS
D019380:Anti-HIV Agents / Q000494:pharmacology; D018076:DNA, Complementary / Q000032:analysis*; D015723:Gene Library; D015696:Gene Products, tat / Q000502:physiology; D016678:Genome; D006678:HIV / Q000254:growth & development*; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D011533:Proviruses / Q000254:growth & development; D034622:RNA Interference; D014158:Transcription, Genetic; D054322:tat Gene Products, Human Immunodeficiency Virus; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D019380:Anti-HIV Agents; D018076:DNA, Complementary; D015696:Gene Products, tat; D020930:MAP Kinase Kinase Kinases; D054322:tat Gene Products, Human Immunodeficiency Virus; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11