Ring finger protein 39 genetic variants associate with HIV-1 plasma viral loads and its replication in cell culture
- Ying-Ju Lin†1, 2,
- Chia-Yen Chen†3,
- Kuan-Teh Jeang4,
- Xiang Liu4,
- Jen-Hsien Wang5,
- Chien-Hui Hung6,
- Hsinyi Tsang7,
- Ting-Hsu Lin1,
- Chiu-Chu Liao1,
- Shao-Mei Huang1,
- Cheng-Wen Lin8,
- Mao-Wang Ho5,
- Wen-Kuei Chien9, 10,
- Jin-Hua Chen9, 10,
- Tsung-Jung Ho2, 11, 12Email author and
- Fuu-Jen Tsai1, 2, 13Email author
© Lin et al.; licensee BioMed Central Ltd. 2014
Received: 3 June 2014
Accepted: 29 July 2014
Published: 5 August 2014
The human immunodeficiency virus (HIV-1) exploits host proteins to complete its life cycle. Genome-wide siRNA approaches suggested that host proteins affect HIV-1 replication. However, the results barely overlapped. RING finger protein 39 (RNF39) has been identified from genome-wide association studies. However, its function during HIV-1 replication remains unclear.
Methods and results
We investigated the relationship between common RNF39 genetic variants and HIV-1 viral loads. The effect of RNF39 protein knockdown or overexpression on HIV-1 replication was then investigated in different cell lines. Two genetic variants were associated with HIV-1 viral loads. Patients with the ht1-GG/GG haplotype presented lower RNF39 expression levels and lower HIV-1 viral load. RNF39 knockdown inhibited HIV-1 expression.
RNF39 protein may be involved in HIV-1 replication as observed in genetic studies on patients with HIV-1 and in in vitro cell cultures.
The human immunodeficiency virus (HIV-1) genome encodes for 15 viral proteins and exploits host cellular proteins to complete its life cycle [1, 2], which includes viral entry, uncoating, reverse transcription, nuclear import, integration, transcription, translation, viral assembly, and virus budding [3–6]. Because of the complicated nature of the viral life cycle and restricted encoded viral proteins, the function of host cellular proteins associated with virus replication remains to be confirmed. Genome-wide siRNA screening approaches have been conducted to identify host cellular proteins that affect HIV-1 replication [7–10]. However, little overlapping was observed between these screening studies. This may be due to diverse experimental conditions, including virus strains, cell line usages, the delivery efficiency of siRNAs or shRNA libraries, and the analysis of RNAi datasets. Therefore, functional characterization of interesting genes and their genetic-clinical correlations in patients with HIV-1 are essential to elucidate the role of host cellular proteins in HIV-1 replication.
Previous genome-wide association studies have mapped to a region close to the ZNRD1 (zinc ribbon domain-containing 1) and RING finger protein 39 (RNF39) associated with HIV-1 disease progression [11, 12]. We have also showed that ZNRD1 genetic variants contribute to HIV-1 clinical course in the Han Chinese population in Taiwan and that ZNRD1 RNA interference-mediated silencing inhibited HIV-1 replication in Jurkat cells . RNF39 encodes a protein containing a specialized type of SPRY domain in its C-terminal that determines viral specificity and restriction potency . It is located within the major histocompatibility complex class I region on chromosome 6. However, its biological function during HIV-1 replication remains unclear.
In this study, we conducted a genetic association study between RNF39 common genetic variants and HIV-1 viral loads in a Han Chinese cohort in Taiwan and evaluated the role of RNF39 in HIV-1 replication. Our results suggest that RNF39 common genetic variants associate with HIV-1 plasma viral loads and may be required for HIV-1 replication.
RNF39 genetic variants, rs3807032, rs3807033, and related haplotypes, associate with HIV-1 viral load levels
Baseline characteristics of patients with HIV-1 in the Han Chinese population in Taiwan
Taiwanese HIV-1 infected patients
No. of participants
Mean age at HIV-1 positive (range), yearsa
Mean plasma HIV-1 viral load (interquartile range), log10 copies/mLb
Effects of RNF39 gene SNPs on plasma HIV-1 viral load in the Han Chinese Population in Taiwan
Taiwanese HIV-1 infected patients
Genotype frequency (No (%))
HIV-1 Viral Load (log10 copies/mL, mean (interquartile range))a
5′ near gene
CG + CC
74 (24.4) + 10 (3.3)
5′ near gene
AG + AA
73 (24.1) + 10 (3.3)
5′ near gene
CG + GG
127 (41.9) + 81 (26.7)
5′ near gene
AG + AA
89 (29.4) + 12 (4.0)
5′ near gene
AG + AA
20 (6.6) + 0 (0.0)
5′ near gene
AG + AA
114 (37.6) + 30 (9.9)
Effects of RNF39 haplotypes on plasma HIV-1 viral load in the Han Chinese Population in Taiwan
Genotype frequency (no (%))
HIV-1 viral load (log10 copies/mL, mean (interquartile range))a
Ht1 (GG/GG, n (%))
Ht2 (GG/CA, n (%))
Ht3 (CA/CA, n (%))
RNF39 affects HIV-1 replication in HEK293T cells
The cDNA overexpression method was further used to evaluate the effect of several proteins on HIV-1 infection after RNF39 knockdown by siRNA. siRNF39-treated 293 T cells were transfected with expression plasmids, including the pZNRD1, pRNF39, and pCMV plasmid. Cells were then infected with NL4-3△G/P-EGFP. As shown in Figure 3C, the number of GFP positive cells infected with NL4-3△G/P-EGFP increased after overexpression of RNF39 or ZNRD1 (188.7% for pRNF39 and 170.7% for pZNDR1, p = 0.004).
RNF39 is also required for HIV-1 replication in Jurkat cells
In the present study, we first showed that plasma HIV-1 viral loads are associated with RNF39 genetic variants in patients infected with HIV-1. Furthermore, we found an association between RNF39 haplotypes and HIV-1 viral loads. Patients with the RNF39 ht1-GG/GG haplotype presented lower levels of HIV-1 viral load. Both SNPs are located in the 5′ regulatory region, which may affect nascent mRNA production or protein expression, thereby modulating HIV-1 production. Patients with the ht1-GG/GG haplotype exhibited lower levels of RNF39 expression. Our results suggest that RNF39 expression knockdown inhibits HIV-1 expression, suggesting that RNF39 is required for viral replication. Genome-wide association studies (GWASs) revealed that human genetic variations, especially in genes located in the MHC region are involved in the control of HIV viral load, CD4 count, or the disease clinical course [11, 16]. A few studies revealed that human genetic variations, especially genes located in the MHC region, close to RNF39, were associated with the control of HIV viral load, CD4 count, and/or the disease clinical course, but the results were still inconsistent [11, 12, 16, 17]. RNF39 SNPs are related to both disease progression and viral load [11, 16]. RNF39 SNPs have been associated with CD4 T-cell count, but not with disease course [12, 17]. We showed that RNF39 gene plays an important role in HIV replication and its genetic variants are associated with plasma viral loads in a Han Chinese cohort. Determinants for host control of infection, based on SNPs, still need to be confirmed among different populations, followed by detailed genomic and functional analyses of the associated region to verify putative SNPs.
By using RNA interference and complementation of RNF39 protein expression, we showed that RNF39 host cellular protein affects HIV-1 replication. These findings are in accordance with the identification of host cellular proteins that contribute to the HIV-1 life cycle [1, 2]. Although Ballana et al. reported that RNF39 downregulation by siRNA did not impair HIV-1 replication in HeLa-derived cell lines , we used both lymphoid and non-lymphoid cell lines to demonstrate that RNF39 actually affects HIV-1 replication. RNF39 antiviral mechanism might be associated with the presence of the SPRY domain in RNF39 protein C-terminal . This SPRY domain determines viral specificity and restriction potency, and is one of the major determinants for the host tropism of HIV-1 and related retroviruses [19–21]. To our knowledge, this is the first study to demonstrate a positive correlation between RNF39 and HIV-1 replication. Our results provide in vitro evidence regarding the role of RNF39 host cellular protein in HIV-1 replication and suggest that this protein may contribute to HIV-1 life cycle. Future studies in primary T cells and macrophages are warranted to confirm its function.
In conclusion, we provided further information that RNF39 is a host cellular protein required for HIV-1 replication in vitro and its genetic variants are associated with HIV-1 viral loads. Our findings emphasize the importance of studying individuals with a range of genetic backgrounds in HIV-1 infection research.
Materials and methods
This study was an observational study. The patients with HIV-1 were recruited from the Section of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan. Voluntary participants provided written informed consent and agreed to provide long-term follow-up clinical, epidemiological data, plasma, and peripheral blood mononuclear cells (PBMCs). Blood was collected by venipuncture. PBMCs were isolated by Ficoll-Histopaque (Sigma Aldrich, Saint Louis, MO, USA, 1077) density gradient centrifugation and frozen until use. HIV-1-antibody-positive individuals were recruited and HIV status was confirmed by quantitative HIV-1 RNA measurement (Roche, Basel, Switzerland; COBAS TaqMan HIV-1 assay v2.0).
HIV-1 viral loads were determined when the patient was examined with the earliest HIV-1 antibody positive result. Patients whose viral loads were measured after the initiation of antiretroviral treatment were excluded from the study. These patients with HIV-1 were (a) naïve for antiretroviral treatment, (b) belonged to the Han Chinese ethnic group, and (c) were willing to provide blood samples for genotyping. The study was approved by the Institutional Review Board of China Medical University Hospital. All participants read and signed informed consent documents.
Detection of RNF39 genetic polymorphisms
RNF39 SNPs were selected from the NCBI SNP database and HAPMAP website [13, 22–24]. Selection criteria were a minor allele frequency >5% in the Han Chinese population and Hardy–Weinberg equilibrium (p > 0.05). A summary of RNF39 gene SNPs information (location, position, rs number, and genotype) is presented in Table 2. Briefly, genomic DNA was extracted from PBMCs according to standard protocols (Genomic DNA kit, Qiagen, Limburg, Netherlands). SNPs were genotyped using a custom-designed VeraCode GoldenGate Genotyping Assay System (Illumina, San Diego, CA, USA) , and genotyping was performed as outlined on the Illumina website (http://www.illumina.com/).
Real-time quantitative PCR
Total RNAs were isolated from PBMCs using the RNeasy Mini kit (Qiagen). RNF39 mRNA relative levels from individuals were measured by qPCR and normalized to HPRT mRNA expression (Universal ProbeLibrary Assay Design Center, Roche). The relative expression levels were expressed as RNF39 mRNA/HPRT mRNA ratio (Figure 1). For human genes, primers and DNA probes were commercially designed and purchased (RNF39 gene, forward primer: 5′-agactgacagccgacctga-3′ and reverse primer: 5′-ctggtggggccagttgta-3′, probe 70 from Universal ProbeLibrary).
Genotypes were obtained by direct count, followed by allele frequency calculations (Table 2). The unpaired Student’s t-test was used for comparison between groups (Tables 2 and 3). Lewontin’s D’ measure was used to estimate the intermarker coefficient of linkage disequilibrium (LD) of our patients with HIV-1 using HAPLOVIEW software . The LD confidence interval was estimated using a resampling procedure and was used to construct the haplotype blocks . Haplotypes were inferred from unphased genotype data by using the Bayesian statistical method available in the program Phase 2.1 [27–29]. All statistical analysis was performed using SPSS (v12.0; IBM, Chicago, IL, USA) for Windows, and graphs were generated using GraphPad Prism version 5.01 for Windows (GraphPad Software, San Diego, California, USA).
Cells and recombinant virus
293 T cells (ATCC, Manassas, VA, USA; accession no. CRL-11268) were cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 100 U/mL penicillin, 100 U/mL streptomycin, and 2 mM L-glutamine (Gibco). Jurkat cells (ATCC; accession number TIB-152) were grown in RPMI-1640 medium supplemented with 10% FBS and 100 U/mL penicillin, 100 U/mL streptomycin, and 2 mM L-glutamine.
HIV-1 pseudotyped virus NL4-3△G/P-EGFP was produced from 293 T cells as previously described . Briefly, cells were cotransfected with three package vectors including pCMV△R8.2 (the package vector), pMD.G (VSV-G expression vector), and pNL4-3:△G/P-EGFP (HIV-1 molecular clone NL4-3 strain with EGFP reporter gene, without viral gag and pol genes). After 48 h of incubation, viruses were collected from the culture supernatant and titrated on 293 T cells based on GFP expression. Cells were infected with NL4-3△G/P-EGFP (multiplicity of infection (moi) = 5) in the presence of 6 μg/mL polybrene (Sigma).
The HIV-1 (pNL4-3) and HTLV-1 k30 molecular clones and the viral Tax gene clone were obtained from the NIH AIDS Research and Reference Reagent Program [30–32]. All media were supplemented with 100 U/mL penicillin, 100 U/mL streptomycin, and 2 mM L-glutamine.
Drug and short interfering RNAs
AZT was commercially obtained (Sigma). Short Interfering RNAs (siRNAs) targeting transcripts for RNF39 (siRNF39: GACUGAGACUCUGGUUGAAGAGAGA) and the non-targeting siRNA control (siNC) were purchased from Invitrogen (Carlsbad, CA, USA).
siRNA or cDNA plasmid transfection
For 293 T cells, cells (2 × 105) were seeded in 24-well plates and cultured for 24 h. siRNAs or cDNA plasmid targeting RNF39 (NM_025236) (Figure 2A,B and Figure 3A,B and C) were mixed with Roche X-tremeGENE Transfection Reagent (Roche) in serum-free medium (OPTI-MEM I, Invitrogen) following the manufacturer’s recommendations. siRNA or cDNA plasmid-transfected 293 T cells were then infected with NL4-3△G/P-EGFP (moi = 5) in the presence of 6 μg/mL polybrene (Sigma) for 36 h. After infection, cells were used for the quantification of EGFP expression by flow cytometry.
For Jurkat cells, cells (2 × 105) were seeded in 24-well plates and cultured for 24 h. siRNAs targeting RNF39 (NM_025236) (Figure 4) were transfected using Amaxa Nucleofector Technology (Lonza, Basel, Switzerland) following the manufacturer’s recommendations. Cells were then recovered and seeded in prewarmed 24-well plates. After 48 h incubation, Jurkat cells were transfected with pNL4-3 or HTLV-1 molecular clone k30 and incubated for another 36 h. Cells were then used for HIV-1 western blot analysis (Figure 4B), HIV-1 p24 antigen enzyme-linked immunosorbent assay (ELISA) (Figure 4C), and HTLV-1 p19 antigen ELISA (Figure 4D).
Reagents and western blot
The anti-HIV-1 antibody was obtained from the NIH AIDS Research and Reference Reagent Program. The anti-beta tubulin antibody was obtained from GeneTex (GeneTex, Irvine, CA, USA; GTX101279). The HTLV-1 p19 ELISA kit and anti-p19 antibody were from Zeptometrix (Buffalo, NY, USA). The experimental protocol for western blot was previously described [33, 34]. Briefly, cells were harvested, washed, and lysed in lysis buffer (50 mM Tris–HCl [pH 7.5], 150 mM NaCl, 5 mM EDTA, 1% Triton X-100, 0.1% SDS) supplemented with protease inhibitor cocktail (Roche). The lysates were resolved by 12% SDS-PAGE and transferred to polyvinylidene fluoride membranes (Millipore, Billerica, MA, USA). The membrane was incubated with primary antibodies overnight at 4°C, and then incubated with alkaline phosphatase-conjugated secondary antibodies (Sigma). Signals were visualized using chemiluminescence following the manufacturer’s protocol (Chemicon, Billerica, MA, USA). Band intensities were quantified using ImageJ software.
The authors wish to thank the Infectious Disease Section, Department of Internal Medicine, China Medical University Hospital (CMUH) for administrative assistance. We also thank Drs. Ya-Hui Chi, Zachary Klase, and Willy W. L. Hong for technical help and suggestions.
Financial support for this research was provided by CMU (CMU100-S-01), CMUH (DMR-103-039; DMR-103-100), and the Republic of China National Science Council (NSC100-2320-B-039-012-MY3).
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