Feng-Liang Liu

High prevalence of HIV, HCV, HBV and co-infection and associated risk factors among injecting drug users in Yunnan province, China.

Objective To estimate the prevalence of HIV, HCV, HBV and co-infection with 2 or 3 viruses and evaluate risk factors among injecting drug users (IDUs) in Yunnan province, China. Methods 2080 IDUs were recruited from 5 regions of Yunnan Province, China to detect the infection status of HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). Statistical analysis was performed to evaluate risk factors related to HIV, HCV and HBV infections. Results The infection rates among all participants were 25.5% for HIV, 77.7% for HCV, 19.2% for HBV, 15% for HIV/HCV, 0.3% for HIV/HBV, 7.8% for HCV/HBV and 7.1% for HIV/HCV/HBV. The prevalence of virus infection varied widely by region in Yunnan of China. Statistical analyses indicated that high prevalence of HIV and HCV among IDUs was positively associated with the duration of drug injection and sharing needles/syringes; besides, HCV infection was associated with the frequency of drug injection. Conclusions HIV, HCV, HBV infections and co-infections were still very prevalent among IDUs in Yunnan province because of drug use behaviors.

Extensive and complex HIV-1 recombination between B ', C and CRF01_AE among IDUs in south-east Asia

Objective:To investigate the subtype characterization of HIV-1 among IDUs in northern Myanmar. Design:A molecular epidemiological investigation was conducted among IDUs in Laza and Maizayang cities of northern Myanmar. Methods:A total of 83 HIV-1-positive serums were collected from consenting IDUs during June to August 2009. HIV-1 p17, pol, vif-env, C2V3 fragments were amplified and sequenced. Phylogenetic and bootscanning analyses were performed. Results:A very high proportion (86.1%) of HIV-1 intersubtype recombinants and very low proportion of subtypes B′ (3.8%), C (7.6%) and CRF01_AE (1.3%) were found in this HIV-infected IDUs cohort. These recombinants cover all four kinds of recombination forms formed among CRF01_AE, B and C. The B/C and CRF01_AE/B/C recombinants are the two most dominant recombinants, accounting for 54.4 and 42.6% of all cases, respectively, and indicating the ongoing generation of extensive and complex HIV-1 recombination among CRF01_AE, B′ and C in northern Myanmar. Intriguingly, most recombinants have different chimeric patterns from each other, forming 64 unique recombination forms (URFs) that are quite distinct from any previously identified circulating recombinant forms (CRFs) and URFs in Asia. Conclusion:The extremely high proportion of intersubtype recombinants, especially CRF01_AE/B′/C recombinants (42.6%), strongly suggests that northern Myanmar is a big forge for HIV-1 recombination among CRF01_AE, B′ and C.

Comparison of HIV-, HBV-, HCV- and Co-Infection Prevalence between Chinese and Burmese Intravenous Drug Users of the China-Myanmar Border Region

Background Co-infection with HIV and HCV and/or HBV is highly prevalent in intravenous drug users (IDUs). Because of the proximity to the “Golden Triangle”, HIV prevalence among the IDUs is very high in the China-Myanmar border region. However, there are few studies about co-infection with HIV and HCV and/or HBV, especially in the region that belongs to Myanmar. Methods 721 IDUs, including 403 Chinese and 318 Burmese, were investigated for their HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) serological status. Statistical analysis was performed to evaluate the differences of the epidemic situation between the Chinese IDUs and the Burmese IDUs. Results Among the Chinese IDUs and the Burmese IDUs, HCV infection was the most prevalent (69.0% vs 48.1%, P<0.001), followed by HBV (51.6% vs 43.1%, P<0.05) and HIV (33.7% vs 27.0%, P>0.05). Besides, there were more HIV-HBV co-infected IDUs (20.1% vs 11.3%, P<0.005), and HIV-HCV co-infected IDUs (31.8% vs 23.9%, P<0.05) in China than in Myanmar, as well as HIV-HBV-HCV triple infection (19.1% vs 10.4%, P<0.005). Conclusion Co-infection with HIV and HCV and/or HBV is highly prevalent among the IDUs in the China-Myanmar border region. The HIV epidemic appears to be in a downward trend, compared with previous reports. However, all infections were more prevalent among the Chinese IDUs than among the Burmese.

An HIV-1 resistance polymorphism in TRIM5α gene among Chinese intravenous drug users.

Background:TRIM5α has species-specific restriction activity against replication of many retroviruses, including HIV-1. Though human also express TRIM5α protein, it is less potent in suppressing infection of HIV-1 than most orthologs of other nonhuman primates. Previous association studies suggested that polymorphisms in TRIM5α gene might protect against HIV-1 infection. However, the exact variation accounting for this protective effect was not certain. Methods:One thousand two hundred ninety-four Chinese intravenous drug users (IDUs), including 1011 Hans and 283 Dai subjects, were investigated for sequence variations in TRIM5α and association with HIV-1 resistance. Resequencing of the putative functional domains in exon2 and exon8 was carried out in 1151 subjects, along with exon2 resequencing in a further 143 HIV-1-infected IDUs. Results:We identified 14 different nucleotide variants, including 4 with minor allele frequency >0.05. We observed that the frequency of 43Y homozygote in seronegative IDUs was significantly higher than that in the HIV-1-infected IDUs, suggesting a protective effect among the homozygote subjects [odds ratio (95% confidence interval) = 0.46 (0.22 to 0.94), P = 0.033, Mantel-Haenszel test]. Conclusions:we concluded that H43Y might account for the HIV-1 resistance due to TRIM5α gene in Chinese IDUs.

Increased expression and dysregulated association of restriction factors and type I interferon in HIV, HCV mono‐ and co‐infected patients

Host restriction factors and type I interferon are important in limiting HIV and HCV infections, yet the role of HIV, HCV mono‐ and co‐infection in regulating these antiviral genes expression is not clear. In this study, we measured the levels of TRIM5α, TRIM22, APOBEC3G, and IFN‐α, ‐β mRNA expression in peripheral blood mononuclear cells of 43 HIV mono‐infected, 70 HCV mono‐infected and 64 HIV/HCV co‐infected patients along with 98 healthy controls. We also quantified HIV and HCV viral loads in mono‐ and co‐infected patients. The results showed that HCV, HIV mono‐ and co‐infection differentially increased TRIM22, APOBEC3G, and IFN‐α, ‐β mRNA expression while the mRNA expression of TRIMα was upregulated only by HCV‐mono infection. HIV/HCV co‐infection was associated with higher viral load, compared to either HIV or HCV mono‐infection. Additionally, we showed TRIMα and TRIM22 positively correlated with IFN‐α, ‐β, which could be dysregulated by HIV, HCV mono‐ and co‐infection. Furthermore, we found TRIM22 negatively correlated with HCV viral load in mono‐infected patients and APOBEC3G positively correlated with HCV viral load in co‐infected patients. Collectively, our findings suggest the potential role of restriction factors in restricting HIV, HCV mono‐ and co‐infection in vivo, which appears to be a therapeutic target for potential drug discovery. J. Med. Virol. 88:987–995, 2016.

Independent Birth of a Novel TRIMCyp in Tupaia belangeri with a Divergent Function from Its Paralog TRIM5

The origin of novel genes and their evolutionary fates are long-standing questions in evolutionary biology. These questions become more complicated for genes conserved across various lineages, such as TRIM5, an antiretroviral restriction factor and a retrovirus capsid sensor in immune signaling. TRIM5 has been subjected to numerous pathogenic challenges and undergone dynamic evolution, making it an excellent example for studying gene diversification. Previous studies among several species showed that TRIM5 gained genetic and functional novelty in a lineage-specific manner, either through gene duplication or a cyclophilin A retrotransposing into the TRIM5 locus, creating the gene fusion known as TRIM5-Cyclophilin A (TRIMCyp). To date, the general pattern of TRIM5 across the mammalian lineage remains elusive. In this study, we surveyed 36 mammalian genomes to verify a potentially novel TRIM5 pattern that uniquely seems to have occurred in tree shrews (Tupaia belangeri), and found that both gene duplication and retrotransposition worked jointly to form a specific TRIM5/TRIMCyp cluster not found among other mammals. Evolutionary analyses showed that tree shrew TRIMCyp (tsTRIMCyp) originated independently in comparison with previously reported TRIMCyps and underwent strong positive selection, whereas no signal of positive selection was detected for other tree shrew TRIM5 (tsTRIM5) genes. Functional assay results suggest a functional divergence between tsTRIMCyp and its closest paralog TRIM5-4, likely reflecting different fates under diverse evolutionary forces. These findings present a rare example of novel gene origination resulting from a combination of gene duplication, retrotransposition, and exon shuffling processes, providing a new paradigm to study genetic innovations and evolutionary fates of duplicated genes.

Association of TRIMCyp and TRIM5α from assam macaques leads to a functional trade-off between HIV-1 and N-MLV inhibition

TRIM5α restricts retroviruses in a species-specific manner. Cyclophilin A was independently retrotransposed into the TRIM5 loci in different species, leading to the generation of antiviral TRIM5-cyclophilin A (TRIMCyp) proteins. Previously, we found that assam macaques express a TRIMCyp chimera (amTRIMCyp), along with a TRIM5α allelic protein (amTRIM5α). Herein, we investigated the antiviral activity of amTRIMCyp and amTRIM5α individually, as well as their interaction and joint effects. amTRIMCyp showed a divergent restriction pattern from amTRIM5α. Although both proteins potently restricted the replication of HIV-1, only amTRIM5α inhibited N-MLV. Remarkably, cellular anti-HIV-1 activity increased when amTRIMCyp and amTRIM5α were coexpressed, indicating a synergistic block of HIV-1 replication. Consistently, PMBCs from heterozygous amTRIM5α/TRIMCyp showed stronger resistance to HIV-1 infection than those from amTRIM5α/TRIM5α homozygotes. The anti-HIV-1 synergistic effect was dependent on the amTRIMCyp-amTRIM5α interaction. In contrast, amTRIMCyp completely abrogated the anti-N-MLV activity mediated by amTRIM5α, showing a dominant-negative effect, indicating that the generation of amTRIMCyp was involved in the trade-off between divergent restriction activities. Our results provide a new paradigm to study functional trade-offs mediated by allelic proteins, a theoretical basis for utilizing animal models with various TRIM5 alleles, as well as novel HIV-1 gene therapy strategies.

High seroprevalence of toxoplasma gondii and HIV-1 co-infection among drug users in Yunnan province, southwest China

Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; The Second People’s Hospital of Yunnan Province, Kunming 650021, China; Yunnan Center for Disease Control and Prevention, Kunming 650022, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China

Tissue Distribution of TRIM5α in Rhesus Monkey and Upregulation in Peripheral Blood Mononuclear Cell by Using Different Stimuli: Tissue Distribution of TRIM5α in Rhesus Monkey and Upregulation in Peripheral Blood Mononuclear Cell by Using Different Stimuli

TRIM5α (tripartite motif protein 5-alpha) protein is a very important restriction factor in rhesus monkey. It can restrict the replication of retroviruses, such as HIV-1 (human immunodeficiency virus type 1), EIAV (equine infectious anemia virus) and FIV (feline immunodeficiency virus). Up to now, there is no report about the tissue distribution of TRIM5α in rhesus monkey. The influence of different stimuli on the expression of TRIM5α mRNA has also not been examined in monkey peripheral blood mononuclear cell (PBMC). In this study, total RNA was extracted from different tissues of a rhesus monkey collected in Yunnan, China, and was quantified using the β-actin gene as the internal reference. The expression levels of TRIM5α mRNA in PBMC that was treated with three conditions (the HIV-GFP-VSVG pseudotyped virus challenged, PMA and Ion-costimulated, anti-CD28 and anti-CD49d antibody-costimulated) were also evaluated at different time points. Our results showed that TRIM5α mRNA expressed broadly in all 21 studied tissues, with the highest level in tissues of immune system and urogenital system and a lower level in nervous system, such as cerebrum and spinal cord. The expression level of the TRIM5α mRNA level in PBMC was upregulated after being activated by the three treatments.

Activation of NF-κB induced by TRIMCyp showing a discrepancy between owl monkey and northern pig-tailed macaque

HighlightsomTRIMCyp induces NF‐&kgr;B activation in a dose‐dependent, but npmTRIMCyp does not.Both omTRIMCyp and npmTRIMCyp can promote AP‐1 and IFN‐&bgr; activation.CypA domain of omTRIMCyp plays an important role in NF‐&kgr;B activation.omTRIMCyp enhances I&kgr;B&agr; and IRF3 phosphorylation, but npmTRIMCyp does not. &NA; TRIMCyp generated by retrotransposition of a cyclophilin A inserting into TRIM5 locus, has been identified in owl monkey and most of Old World monkeys (OWM). Owl monkey TRIMCyp (omTRIMCyp) inhibits HIV‐1 infection by direct interaction with viral capsid and indirect innate immune induction, whereas most of TRIMCyps from OWM cannot inhibit HIV‐1, and the impact of which on immunoregulation is largely unknown. Here we reported that omTRIMCyp induces NF‐&kgr;B, AP‐1 and IFN‐&bgr; activation in a dose‐dependent manner, while TRIMCyp from northern pig‐tailed macaque (npmTRIMCyp) does not activate NF‐&kgr;B and moderately enhances AP‐1 and IFN‐&bgr; activities. The Cyclophilin A (CypA) domain plays an important role in omTRIMCyp‐mediated NF‐&kgr;B activation, and RBCC domains have a synergetic effect. We further indicated the mechanism by which npmTRIMCyp unable to activate NF‐&kgr;B is that npmTRIMCyp hardly phosphorylates I&kgr;B&agr;, different from omTRIMCyp which dramatically induces I&kgr;B&agr; phosphorylation. Ubiquitination activity of omTRIMCyp was greater than npmTRIMCyp, although both could be ubiquitylated. Given that npmTRIMCyp neither interacts with viral capsid resulting in susceptibility to HIV‐1 infection, nor activates NF‐&kgr;B that is indispensable to HIV‐1 provirus transcription, we proposed a model that npmTRIMCyp may play an important role in HIV‐1 infected northern pig‐tailed macaque with latency.