Publicación: A 6-amino acid insertion/deletion polymorphism in the mucin domain of TIM-1 confers protections against HIV-1 infection.
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Universidad Cooperativa de Colombia, Facultad de Ciencias de la Salud, Medicina, Medellín y Envigado
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2016-09-18
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We investigated whether a 6-amino acid insertion/deletion polymorphism in the mucin domain of TIM-1 (T-cell immunoglobulin and mucin domain 1), modulates susceptibility to HIV-1 infection. The polymorphism was genotyped in three case/control cohorts of HIV-1 exposed seronegative individuals (HESN) and HIV-1 infected subjects from Italy, Peru, and Colombia; data from a Thai population were retrieved from the literature. Across all cohorts, homozygosity for the short TIM-1 allele was more common in HESNs than in HIV-1 infected subjects. A metaanalysis of the four association analyses yielded a p value of 0.005. In vitro infection assays of CD4þ T lymphocytes indicated that homozygosity for the short allele is associated with lower rate of HIV-1 replication. These results suggest that the deletion allele protects from HIV-1 infection with a recessive effect.
Descripción general
Infection of cells by enveloped viruses is a multi-step process requiring both the binding of viral glycoproteins to specific cellular receptors/coreceptors and less specific interactions with accessory molecules whose main function is to locate the virus closer to its receptor(s) [1]. Among such attachment factors, a key role has been attributed to the TIM (T-cell immunoglobulin and mucin domain containing) family receptors, cell surface glycoproteins that control both innate and acquired immune responses during allergy, asthma, tolerance, autoimmunity, as well as viral infections [2].
In the human genome, three genes (HAVCR1, HAVCR2 and TIMD4) encode TIM proteins (TIM-1, TIM-3, and TIM-4, respectively). Structurally, all TIM proteins have a conserved ectodomain consisting of an immunoglobulin (IgV)-like domain and an heavily glycosylated mucin-like domain, anchored to the cell through a transmembrane domain followed by a cytoplasmic tail [3]. TIM-1, in particular, is mostly
expressed by hepatocytes and lymphoid cells, preferentially Th2 cells, and is a key T-cell costimulatory molecule that controls T cell activation [4,5]. Human TIM-1, originally identified as the receptor for
hepatitis A virus (HAV) [6], promotes the entry of a wide variety of enveloped viruses in host cells [7]. Virus internalization occurs when TIM binds phosphatidylserine (PtdSer) on the viral envelope; this process seems to be independent of viral glycoprotein interaction with cellular receptors [7,8]. A
recent analysis of the role of TIM-1 domains indicated that, whereas the IgV domain is essential for virus binding and internalization, the mucin-like domain also plays a key role in enhancing viral entry [8]. Specifically, the use of deletion mutants indicated that a stalk of adequate length is necessary
to form an extended structure that places the IgV domain within the appropriate distance from the host cell membrane, thus allowing optimal interactions with the virus [8]. Interestingly, the HAVCR1 gene is highly polymorphic in human populations. In particular, natural selection has maintained high nucleotide diversity in exon 4, which encodes a portion of the mucin-like domain [9]. The selective pressure
acting on this region is believed to be virus-mediated, suggesting that polymorphisms in exon 4 modulate viral infection susceptibility and/or diseases severity. In fact, an 18-bp insertion/deletion
polymorphism in the exon, causing a six amino acid insertion/deletion variant (157ins/delMTTTVP), was associated with the risk to develop acute liver failure following HAV infection [10]; the same variant was found to modulate AIDS progression in HIV-1 infected subjects [11]. Notably, in both studies the deleted (short) allele of 157ins/delMTTTVP exerted a protective effect. In the HAV study, having one or two copies of the long form of TIM1 was associated with a greater risk to develop severe liver failure, indicating that the protective effect of the short allele is recessive [10]. These data are in line
with the observation that the length of the mucin-like domain is critical for enhancing enveloped virus entry [8]. In fact, TIM-1 molecules with a short mucin-like domain (157delMTTTVP) bind HAV less efficiently than those with a long domain (157insMTTTVP) [10]. Herein we assessed whether the HAVCR1 (Hepatitis A virus cellular receptor 1) 18-bp insertion/deletion polymorphism modulates susceptibility to HIV-1 infection in three independent cohorts of HIV-1 exposed seronegative (HESN) individuals. Results indicated that homozygosity for the short allele is associated with natural protection from infection and lower rate of HIV-1 replication in CD4þ T lymphocytes