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

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.

The Host Heat Shock Protein MRJ/DNAJB6 Modulates Virus Infection

“…These observations together suggest that a higher L/S ratio of MRJ may promote HIV infection (Figure 1C, HIV). A cohort study reveals that HIV-infected individuals indeed exhibit a slightly higher level of MRJ-L in macrophages than healthy subjects (Chiang et al, 2014), supporting the positive role of MRJ-L in HIV-1 infection. It is speculated that ciselement polymorphisms of MRJ that favor L isoform expression may increase the probability of HIV infection (Ko et al, 2018).…”

“…For integration, HIV establishes the pre-integration complex (PIC), consisting of the cDNA that is converted from its genomic RNA and several cellular and viral proteins including the viral protein R (Vpr). Vpr participates in proviral integration into the host genome (Chiang et al, 2014;Pirrone et al, 2014). MRJ-L facilitates nuclear localization of the HIV-1 pre-integration complex via its direct interaction with Vpr (Chiang et al, 2014).…”

“…Vpr participates in proviral integration into the host genome (Chiang et al, 2014;Pirrone et al, 2014). MRJ-L facilitates nuclear localization of the HIV-1 pre-integration complex via its direct interaction with Vpr (Chiang et al, 2014). As compared to MRJ-L, MRJ-S displays a relatively weak activity in nuclear localization of Vpr/Vpx likely due to its lack of the C-terminal NLS of MRJ-L (Cheng et al, 2008;Chiang et al, 2014).…”

“…MRJ-L facilitates nuclear localization of the HIV-1 pre-integration complex via its direct interaction with Vpr (Chiang et al, 2014). As compared to MRJ-L, MRJ-S displays a relatively weak activity in nuclear localization of Vpr/Vpx likely due to its lack of the C-terminal NLS of MRJ-L (Cheng et al, 2008;Chiang et al, 2014). Notably, mutations in the HPD motif of MRJ-L disrupt the activity of MRJ-L in facilitating Vpx (or HIV) nuclear import, indicating the involvement of Hsp70 (Cheng et al, 2008).…”

Biomarkers of HIV Susceptibility and Disease Progression

“…In the manuscript by Chiang et al within this issue of EBioMedicine , a new host factor is described as playing a role in HIV-1 susceptibility ( Chiang et al, 2014 ). This host factor, MRJ-L, is the large splice isoform of DNAJB6 (a homolog of heat shock protein 40) and the authors state that it has been shown to interact with Vpr, however this data, to date has not been published and therefore this point is in need of further detailed exploration.…”