Investigating cellular HIV resistance to understand “Elite controllers”?

Yong-Hui Zheng, Ph.D. Associate Professor Biomedical Physical Science Building Department of Microbiology and Molecular Genetics Michigan State University East Lansing, MI Interview with:
Yong-Hui Zheng, Ph.D.
Associate Professor
Biomedical Physical Science Building
Department of Microbiology and Molecular Genetics
Michigan State University
East Lansing, MI 48824-4320 

Medical Research: What is the background for this study? What are the main findings?

 Dr. Zheng: Although HIV-1 has caused one of the most devastating pandemics by inducing AIDS, this virus failed to induce the disease in a small cohort of patients, who are known as “Elite controllers”. The secrete of the viral resistance in these individuals may point the direction of a cure for AIDS, which is still not available in the current antiretroviral therapies.   We started to study HIV resistance using human CD4+ T cells as a model system, because these cells are primary targets for HIV-1 infection. We successfully identified a highly HIV-resistant cell line CEM.NKR, where HIV-1 replication is decreased by almost 1,000-fold. Understanding of the resistant mechanism has been the primary interest in our laboratory, and we have published a series of papers to elucidate how the HIV-1 replication is inhibited in these cells.

Our initial findings uncovered that HIV-1 is able to enter these cells, but fails to regenerate infectious virions. Further investigation showed that although the virus could make the other viral proteins, it fails to express the viral envelope (Env) glycoprotein. Most viruses have an envelope to cover their protein capsids, where viral spikes are anchored. These spikes are made from the Env glycoproteins, which are required for the virus to penetrate into cells and start infection. Thus, identifying the pathway that specifically inhibits the Env expression will open a new avenue for antiretroviral therapies.

In the present paper, we found that the endoplasmic reticulum class I α-mannosidase (ERManI) initiates the Env inhibition process. ERManI is a host enzyme that is involved in protein N-glycosylation. When the ERManI expression is up-regulated, it targets Env to the ER-associated protein degradation (ERAD) pathway, resulting in Env degradation and inhibition of HIV-1 replication.

Medical Research: What should clinicians and patients take away from your report?

Dr. Zheng: These findings suggested that ERManI could contribute to the natural host resistance to HIV-1 infection. It would be interesting to further investigate the correlation between the ERManI expression levels and viral loads in HIV patients. An inverse correlation would further confirm its important role in the natural resistance.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Zheng: ERManI is an unstable protein and expressed at low levels in mammalian cells. We are planning to develop a technology to boost the ERMani expression, and test whether HIV-1 replication could be eradicated by this technology.


Tao Zhou, Dylan A. Frabutt, Kelley W. Moremen, Yong-Hui Zheng.ERManI (Endoplasmic Reticulum Class I α-Mannosidase) Is Required for HIV-1 Envelope Glycoprotein Degradation via Endoplasmic Reticulum-associated Protein Degradation Pathway. Journal of Biological Chemistry, 2015; 290 (36): 22184 DOI:10.1074/jbc.M115.675207

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Yong-Hui Zheng, Ph.D. (2015). Investigating “Elite controllers” To Understand HIV Resistance