Submitted October 22, 2008
Accepted March 5, 2009
Gram positive bacteria enhance HIV-1 susceptibility in Langerhans cells, but not in dendritic cells, via TLR activation
Youichi Ogawa, Tatsuyoshi Kawamura*, Tetsuya Kimura, Masahiko Ito, Andrew Blauvelt, and Shinji Shimada
Department of Dermatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
Department of Retrovirology and Self-Defense, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
Department of Microbiology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
Departments of Dermatology and Molecular Microbiology & Immunology, Oregon Health & Science University and the Dermatology Service, Veterans Affairs Medical Center, Portland, OR, United States
* Corresponding author; email: tkawa{at}yamanashi.ac.jp.
While numerous studies have shown a higher risk of acquiring HIV infection in the presence of other sexually transmitted diseases (STDs), the biologic mechanisms responsible for enhanced HIV acquisition are unclear. Since Langerhans cells (LCs) are suspected to be the initial HIV targets after sexual exposure, we studied whether microbial components augment HIV infection in LCs by activating TLR and NOD pattern recognition receptors. We found that TLR1/2 and TLR2/6 agonists dramatically enhanced both HIV susceptibility and replication in immature monocyte-derived LCs, whereas TLR3-5, TLR7-9, and NOD1, 2 agonists did not significantly affect HIV infection. The same infection-enhancing effects were observed when LCs were incubated with other related bacterial components as well as with whole Gram+ bacteria. In resident LCs in human skin, TLR2 agonists also significantly increased HIV susceptibility. By contrast, TLR2 agonists and related bacterial components decreased HIV susceptibility in monocyte-derived dendritic cells (DCs). We found that TLR2 activation of LCs, but not DCs, resulted in a significant down-regulation of APOBEC3G, which is a cellular restriction factor for HIV. Given these data, we hypothesize that ligation of TLR2 by Gram+ bacterial products may underlie enhanced sexual transmission of HIV that occurs with concomitant bacterial STD infections.
