The envelope gene of transmitted HIV-1 resists a late interferon gamma-induced block

TY - JOUR

T1 - The envelope gene of transmitted HIV-1 resists a late interferon gamma-induced block

AU - Rihn, Suzannah J.

AU - Foster, Toshana

AU - Busnadiego, Idoia

AU - Aziz, Muhamad Afiq

AU - Hughes, Joseph

AU - Neil, Stuart

AU - Wilson, Sam J.

PY - 2017/4

Y1 - 2017/4

N2 - Type I interferon (IFN) signaling engenders an antiviral state that likely plays an important role in constraining HIV-1 transmission and contributes to defining subsequent AIDS pathogenesis. Type II IFN (IFN-γ) also induces an antiviral state but is often primarily considered to be an immunomodulatory cytokine. We report that IFN-γ stimulation can induce an antiviral state that can be both distinct from that of type I interferon and can potently inhibit HIV-1 in primary CD4+ T cells and a number of human cell lines. Strikingly, we find that transmitted/founder (TF) HIV-1 viruses can resist a late block that is induced by type II IFN, and the use of chimeric IFN-γ-sensitive/resistant viruses indicates that interferon resistance maps to the env gene. Simultaneously, in vitro evolution also revealed that just a single amino acid substitution in the envelope can confer substantial resistance to IFN-mediated inhibition. Thus, the env gene of transmitted HIV-1 confers resistance to a late block that is phenotypically distinct from blocks previously described to be resisted by env and is therefore mediated by unknown IFN-γ-stimulated factor(s) in human CD4+ T cells and cell lines. This important unidentified block could play a key role in constraining HIV-1 transmission.

AB - Type I interferon (IFN) signaling engenders an antiviral state that likely plays an important role in constraining HIV-1 transmission and contributes to defining subsequent AIDS pathogenesis. Type II IFN (IFN-γ) also induces an antiviral state but is often primarily considered to be an immunomodulatory cytokine. We report that IFN-γ stimulation can induce an antiviral state that can be both distinct from that of type I interferon and can potently inhibit HIV-1 in primary CD4+ T cells and a number of human cell lines. Strikingly, we find that transmitted/founder (TF) HIV-1 viruses can resist a late block that is induced by type II IFN, and the use of chimeric IFN-γ-sensitive/resistant viruses indicates that interferon resistance maps to the env gene. Simultaneously, in vitro evolution also revealed that just a single amino acid substitution in the envelope can confer substantial resistance to IFN-mediated inhibition. Thus, the env gene of transmitted HIV-1 confers resistance to a late block that is phenotypically distinct from blocks previously described to be resisted by env and is therefore mediated by unknown IFN-γ-stimulated factor(s) in human CD4+ T cells and cell lines. This important unidentified block could play a key role in constraining HIV-1 transmission.

KW - Envelope

KW - HIV-1

KW - Interferons

KW - Restriction factors

KW - Transmitted/founder

KW - Type II interferon

UR - http://www.scopus.com/inward/record.url?scp=85015153527&partnerID=8YFLogxK

U2 - 10.1128/JVI.02254-16

DO - 10.1128/JVI.02254-16

M3 - Article

AN - SCOPUS:85015153527

SN - 0022-538X

VL - 91

JO - Journal of Virology

JF - Journal of Virology

IS - 7

M1 - e02254-16

ER -