Abstract
Tetherin is a membrane protein of unusual topology expressed from rodents to humans that accumulates enveloped virus particles on the surface of infected cells. However, whether this ‘tethering’ activity promotes or restricts retroviral spread during acute retrovirus infection in vivo is controversial. We report here the identification of a single nucleotide polymorphism in the Tetherin gene of NZW/LacJ (NZW) mice that mutated the canonical ATG start site to GTG. Translation of NZW Tetherin from downstream ATGs deleted a conserved dual-tyrosine endosomal sorting motif, resulting in higher cell surface expression and more potent inhibition of Friend retrovirus release compared to C57BL/6 (B6) Tetherin in vitro. Analysis of (B6×NZW)F1 hybrid mice revealed that increased Tetherin cell surface expression in NZW mice is a recessive trait in vivo. Using a classical genetic backcrossing approach, NZW Tetherin expression strongly correlated with decreased Friend retrovirus replication and pathogenesis. However, the protective effect of NZW Tetherin was not observed in the context of B6 Apobec3/Rfv3 resistance. These findings identify the first functional Tetherin polymorphism within a mammalian host, demonstrate that Tetherin cell surface expression is a key parameter for retroviral restriction, and suggest the existence of a restriction factor hierarchy to counteract pathogenic retrovirus infections in vivo.
Highlights
In order to infect and persist in the host, retroviruses such as HIV-1 encode proteins that counteract innate resistance genes that are referred to as ‘‘restriction factors’’
Significant portions of the human and mouse genomes are comprised of retroviral sequences, revealing the long history of conflict between mammalian hosts and retroviruses that led to the evolution of host restriction factors
Nucleotide mutations in restriction factor genes provide a glimpse of this ongoing evolutionary process, but studies that directly probe the impact of restriction factor mutations during retrovirus infection are limited
Summary
In order to infect and persist in the host, retroviruses such as HIV-1 encode proteins that counteract innate resistance genes that are referred to as ‘‘restriction factors’’. Host restriction factors have the potential to directly interfere with specific steps of the retrovirus life cycle and have been the subject of intense study in the last decade. In this regard, mechanistic studies on how the HIV-1 Vpu protein promotes virion release in vitro resulted in the discovery of the long-sought ‘Tetherin’ molecule [1,2]. Tetherin-driven retrovirus evolution in the SIV or SHIV lentivirus infection models [11,12] suggested that Tetherin was an antiretroviral factor. Resolving these opposing views may require pathogenic retrovirus infection studies that isolate the Tetherin gene in vivo
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