An HIV-1 resistance polymorphism in TRIM5α gene among Chinese intravenous drug users.
ABSTRACT 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.
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.
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].
we concluded that H43Y might account for the HIV-1 resistance due to TRIM5α gene in Chinese IDUs.
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ABSTRACT: TRIM5 is a restriction factor that blocks retrovirus infection soon after the virion core enters the cell cytoplasm. Restriction activity is targeted to the virion core via recognition of the capsid protein lattice that encases the viral genomic RNA. In common with all of the many TRIM family members, TRIM5 has RING, B-box, and coiled-coil domains. As an E3 ubiquitin ligase TRIM5 cooperates with the heterodimeric E2, UBC13/UEV1A, to activate the TAK1 (MAP3K7) kinase, NF-κB and AP-1 signaling, and the transcription of inflammatory cytokines and chemokines. TAK1, UBC13, and UEV1A all contribute to TRIM5-mediated retrovirus restriction activity. Interaction of the carboxy-terminal PRYSPRY or cyclophilin domains of TRIM5 with the retroviral capsid lattice stimulates the formation of a complementary lattice by TRIM5, with greatly increased TRIM5 E3 activity, and host cell signal transduction. Structural and biochemical studies on TRIM5 have opened a much needed window on how the innate immune system detects the distinct molecular features of HIV-1 and other retroviruses.Current opinion in virology. 04/2012; 2(2):142-50.
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ABSTRACT: Virus infections are a major global public health concern, and only via substantial knowledge of virus pathogenesis and antiviral immune responses can we develop and improve medical treatments, and preventive and therapeutic vaccines. Innate immunity and the shaping of efficient early immune responses are essential for control of viral infections. In order to trigger an efficient antiviral defense, the host senses the invading microbe via pattern recognition receptors (PRRs), recognizing distinct conserved pathogen-associated molecular patterns (PAMPs). The innate sensing of the invading virus results in intracellular signal transduction and subsequent production of interferons (IFNs) and proinflammatory cytokines. Cytokines, including IFNs and chemokines, are vital molecules of antiviral defense regulating cell activation, differentiation of cells, and, not least, exerting direct antiviral effects. Cytokines shape and modulate the immune response and IFNs are principle antiviral mediators initiating antiviral response through induction of antiviral proteins. In the present review, I describe and discuss the current knowledge on early virus-host interactions, focusing on early recognition of virus infection and the resulting expression of type I and type III IFNs, proinflammatory cytokines, and intracellular antiviral mediators. In addition, the review elucidates how targeted stimulation of innate sensors, such as toll-like receptors (TLRs) and intracellular RNA and DNA sensors, may be used therapeutically. Moreover, I present and discuss data showing how current antimicrobial therapies, including antibiotics and antiviral medication, may interfere with, or improve, immune response.Viruses 01/2013; 5(2):470-527. · 2.51 Impact Factor
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ABSTRACT: HIV and human defense mechanisms have co-evolved to counteract each other. In the process of infection, HIV takes advantage of cellular machinery and blocks the action of the host restriction factors (RF). A small subset of HIV+ individuals control HIV infection and progression to AIDS in the absence of treatment. These individuals known as long-term non-progressors (LNTPs) exhibit genetic and immunological characteristics that confer upon them an efficient resistance to infection and/or disease progression. The identification of some of these host factors led to the development of therapeutic approaches that attempted to mimic the natural control of HIV infection. Some of these approaches are currently being tested in clinical trials. While there are many genes which carry mutations and polymorphisms associated with non-progression, this review will be specifically focused on HIV host RF including both the main chemokine receptors and chemokines as well as intracellular RF including, APOBEC, TRIM, tetherin, and SAMHD1. The understanding of molecular profiles and mechanisms present in LTNPs should provide new insights to control HIV infection and contribute to the development of novel therapies against AIDS.Frontiers in Immunology 01/2013; 4:343.