By Nancy Parrish, Staff Writer
The human immunodeficiency virus (HIV) targets specific immune cells in the body known as macrophages because these are the cells that eliminate foreign material such as bacteria or viruses. HIV is able to reproduce and spread throughout the body if it can avoid destruction by macrophages.
A recent study by Lue Dai, Ph.D., and colleagues revealed that the human cytokine IL-27 helps promote the body’s production of macrophages that are resistant to HIV. The study further found that IL-27 suppresses a gene known as SPTBN1, which facilitates the survival of HIV cells. This breakthrough research was recently published in the Journal of Experimental Medicine.
The new findings suggest that using IL-27 to modulate the SPTBN1 level “renders human macrophages resistant to HIV-1 infection,” said Dai, a postdoctoral fellow in the Laboratory of Human Retrovirology (LHR), Applied and Developmental Research Directorate, SAIC-Frederick. Because treatment with IL-27 does not interfere with the viability or functionality of macrophages, he said, it could be a promising therapeutic candidate to prevent HIV-1 infection.
The next step, he said, is to develop a preclinical trial to assess the anti-HIV effect of IL-27 in vivo, using an animal model.
Long-Term Research Interest
Dai received his Ph.D. in immunology and virology at the University of Massachusetts Medical School, where he first began investigating HIV. “It then became my long-term research interest to understand how host factors impact HIV infection,” he said. In 2010, he joined LHR, where he continues his research to “identify the host target of IL-27 which blocks HIV infection in macrophages.”
He says he owes the success of his current research to a “collaborative effort” among his supervisor, Tomozumi Imamichi, Ph.D., head of LHR, H. Clifford Lane, M.D., National Institute of Allergy and Infectious Diseases, colleagues in the Clinical Services Program, SAIC-Frederick, and collaborators in the Optical Microscopy and Analysis Laboratory, SAIC-Frederick. “[They] have offered great support and assistance to help me advance the project rapidly and smoothly,” he noted. “It is a once-in-a-lifetime experience to make new discoveries with such a strong supportive team.”
IL-27 Inhibits HIV-1 Infection in Human Macrophages by Down-Regulating Host Factor SPTBN1 during Monocyte to Macrophage Differentiation
Lue Dai, Kristy B. Lidie, Qian Chen, Joseph W. Adelsberger, Xin Zheng, DaWei Huang, Jun Yang, Richard A. Lempicki, Tauseef Rehman, Robin L. Dewar, Yanmei Wang, Ronald L. Hornung, Kelsey A. Canizales, Stephen J. Lockett, H. Clifford Lane, and Tomozumi Imamichi
The susceptibility of macrophages to HIV-1 infection is modulated during monocyte differentiation. IL-27 is an anti-HIV cytokine that also modulates monocyte activation. In this study, we present new evidence that IL-27 promotes monocyte differentiation into macrophages that are nonpermissive for HIV-1 infection. Although IL-27 treatment does not affect expression of macrophage differentiation markers or macrophage biological functions, it confers HIV resistance by down-regulating spectrin β nonerythrocyte 1 (SPTBN1), a required host factor for HIV-1 infection. IL-27 down-regulates SPTBN1 through a TAK-1–mediated MAPK signaling pathway. Knockdown of SPTBN1 strongly inhibits HIV-1 infection of macrophages; conversely, overexpression of SPTBN1 markedly increases HIV susceptibility of IL-27–treated macrophages. Moreover, we demonstrate that SPTBN1 associates with HIV-1 gag proteins. Collectively, our results underscore the ability of IL-27 to protect macrophages from HIV-1 infection by down-regulating SPTBN1, thus indicating that SPTBN1 is an important host target to reduce HIV-1 replication in one major element of the viral reservoir.
Editor's note: Platinum Highlight articles are noteworthy publications selected periodically by Dr. Craig Reynolds, associate director, National Cancer Institute, from among the most recently published Platinum Publications.