A 6-amino acid insertion/deletion polymorphism in the mucin domain of TIM-1 confers protections against HIV-1 infection.

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 at...

Full description

Autores:
Biasin, Mara
Sironi, Manuela
Saulle, Irma
Pontremoli, Chiara
Garziano, Micaela
Cagliani, Rachele
Trabattoni, Daria
Caputo, Sergio Lo
Vichi, Francesca
Mazzotta, Francesco
Forni, Diego
Riva, Stefania
Aguilar Jiménez, Wbeimar
Cedeño, Samandhy
Sanchez, Jorge
Brander, Christian
Zapata Builes, Wildeman
Rugeles López, María Teresa
Clerici, Mario
Tipo de recurso:
Article of journal
Fecha de publicación:
2016
Institución:
Universidad Cooperativa de Colombia
Repositorio:
Repositorio UCC
Idioma:
OAI Identifier:
oai:repository.ucc.edu.co:20.500.12494/5667
Acceso en línea:
https://hdl.handle.net/20.500.12494/5667
Palabra clave:
HIV
Resistance to infection
Polymorphism
TIM-1
HESN
Rights
openAccess
License
http://purl.org/coar/access_right/c_abf2
Description
Summary: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