Large Isoform of Mammalian Relative of DnaJ is a Major Determinant of Human Susceptibility to HIV-1 Infection

Yu-Ping Chiang,Wang-Huei Sheng,Pei-Lan Shao,Ya-Hui Chi,Yi-Ming Arthur Chen,Szu-Wei Huang,Hsiu-Ming Shih,Luan-Yin Chang,Chun-Yi Lu,Shan-Chwen Chang,Chien-Ching Hung,Li-Min Huang

doi:10.1016/j.ebiom.2014.10.002

Abstract

SummaryIndividual differences in susceptibility to human immunodeficiency virus type 1 (HIV-1) infection have been of interest for decades. We aimed to determine the contribution of large isoform of Mammalian DnaJ (MRJ-L), a HIV-1 Vpr-interacting cellular protein, to this natural variation. Expression of MRJ-L in monocyte-derived macrophages was significantly higher in HIV-infected individuals (n = 31) than their uninfected counterparts (n = 27) (p = 0.009). Fifty male homosexual subjects (20 of them are HIV-1 positive) were further recruited to examine the association between MRJ-L levels and occurrence of HIV infection. Bayesian multiple logistic regression revealed that playing a receptive role and increased levels of MRJ-L in macrophages were two risk factors for HIV-1 infection. A 1% rise in MRJ-L expression was associated with a 1.13 fold (95% CrI 1.06–1.29) increase in odds of contracting HIV-1 infection. Ex vivo experiments revealed that MRJ-L facilitated Vpr-dependent nuclear localization of virus. Infection of macrophage-tropic strain is a critical step in HIV-1 transmission. MRJ-L is a critical factor in this process; hence, subjects with higher macrophage MRJ-L levels are more vulnerable to HIV-1 infection.

Highlights

More than 30 million individuals worldwide are currently infected with human immunodeficiency virus type 1 (HIV-1), the cause of acquired immunodeficiency syndrome (AIDS), with 1.7 million deaths occurring from AIDS in 2011 (World Health Organization, 2011)
Prompted by the notion that DNAJ is a heat shock protein which may contribute to HIV-1 replication, we investigated the expression of DNAJB6 in lymphocytes and monocyte-derived macrophages (MDMs) which are considered the major targets of early HIV-1 infection
Based on data from cells of 27 uninfected and 31 HIV-1-infected donors [median age was 25 years, median CD4 count was 371/μL and median plasma HIV RNA load was 18,400 copies/mL] as well as from cultured T-cell lines, we noted that MRJ-S was found in all monocytes, macrophages, and cultured cell lines, while MRJ-L was uniformly absent from monocytes (Fig. 1a, b)

Summary

Introduction

More than 30 million individuals worldwide are currently infected with human immunodeficiency virus type 1 (HIV-1), the cause of acquired immunodeficiency syndrome (AIDS), with 1.7 million deaths occurring from AIDS in 2011 (World Health Organization, 2011). Combination antiretroviral therapy is successful in controlling the disease progression of HIV infection. Alternative strategies to control HIV-1 infection are highly desirable. These may include manipulation of the immune response and other host factors. Prophylactic HIV-1 vaccines do not appear to show immediate promise, following the failure of a recent clinical trial (Cohen, 2007). Manipulation of host proteins is currently being evaluated, as demonstrated by a study to modify the CCR5 receptor (Didigu et al, 2014). This is a promising way to complement the current antiretroviral therapy. Its success relies on our understanding of the interaction between HIV-1 and cellular proteins

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