Abstract
Abstract
Simian-human immunodeficiency viruses (SHIVs) are widely used to model HIV-1 infection in macaques, yet most SHIVs encoding circulating HIV-1 envelope glycoproteins (Env) replicate poorly because of inefficient use of macaque CD4 and sensitivity to host antiviral responses. During adaptation to macaques, Env is therefore subject to multiple selective pressures to improve receptor utilization while maintaining function in the face of host immune restriction. Type I interferon (IFN) is a major component of the host antiviral response during acute infection, and IFN resistance increases during SHIV adaptation to macaques through serial passage. However, the viral determinants of this resistance have remained unclear. Here, we show that serial passage of a lineage of SHIVs in macaques selected Env variants with markedly increased resistance to IFN-α and enhanced replication in macaque CD4
+
T lymphocytes. IFN-α resistance mapped principally to loss of two highly conserved N-linked glycans at N197 and N276 near the CD4-binding site. Glycan loss altered the conformational landscape of virus-associated Env, enhanced macaque CD4-dependent entry and membrane fusion without increasing human CD4-dependent entry, and reduced incorporation of the IFN-inducible restriction factors IFITM3 and IFITM3A into progeny virions. Depletion of IFITM3/3A rendered the parental SHIV highly resistant to IFN-α and abolished differential IFN-α sensitivity among parental, adapted, and glycan-loss viruses. These findings reveal that loss of receptor-proximal Env glycans can simultaneously improve utilization of a heterologous CD4 receptor and promote escape from IFN-mediated restriction, linking receptor adaptation and innate immune evasion during lentiviral adaptation to a new host.
Significance
Simian-human immunodeficiency viruses (SHIVs) are essential for modeling HIV-1 infection in macaques, but their adaptation to macaques requires HIV-1 envelope glycoprotein (Env) to overcome species-specific barriers to replication. We show that loss of two conserved Env glycans selected during macaque passage simultaneously improves macaque CD4 usage and promotes escape from IFITM-mediated restriction. These findings reveal that receptor incompatibility and innate immune restriction can impose convergent selective pressures on Env, allowing receptor adaptation and innate immune escape to arise through the same Env changes rather than independent evolutionary solutions. More broadly, they identify the HIV-1 glycan shield as a functional interface linking receptor usage, membrane fusion, and resistance to host antiviral defenses during cross-species adaptation.