A cellular trafficking signal in the SIV envelope protein cytoplasmic domain is strongly selected for in pathogenic infection

Abstract

The HIV/SIV envelope glycoprotein (Env) cytoplasmic domain contains a highly conserved Tyr-based trafficking signal that mediates both clathrin-dependent endocytosis and polarized sorting. Despite extensive analysis, the role of these functions in viral infection and pathogenesis is unclear. An SIV molecular clone (SIVmac239) in which this signal is inactivated by deletion of Gly-720 and Tyr-721 (SIVmac239ΔGY), replicates acutely to high levels in pigtail macaques (PTM) but is rapidly controlled. However, we previously reported that rhesus macaques and PTM can progress to AIDS following SIVmac239ΔGY infection in association with novel amino acid changes in the Env cytoplasmic domain. These included an R722G flanking the ΔGY deletion and a nine nucleotide deletion encoding amino acids 734–736 (ΔQTH) that overlaps the rev and tat open reading frames. We show that molecular clones containing these mutations reconstitute signals for both endocytosis and polarized sorting. In one PTM, a novel genotype was selected that generated a new signal for polarized sorting but not endocytosis. This genotype, together with the ΔGY mutation, was conserved in association with high viral loads for several months when introduced into naïve PTMs. For the first time, our findings reveal strong selection pressure for Env endocytosis and particularly for polarized sorting during pathogenic SIV infection in vivo.

Epistatic pathways can drive HIV-1 escape from integrase strand transfer inhibitors

“…Moreover, these glycans contribute to correct Env glycoprotein folding, processing, antigenicity, and particle infectivity [reviewed in (23)]. The cytoplasmic tails (CTs) of lentiviral gp41 transmembrane glycoproteins also play important roles in a variety of aspects of Env function and contribute to viral pathogenesis (24)(25)(26).…”

Biphasic decay of intact SHIV genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir

“…Non-human primates (NHPs), especially Indian-origin and Chinese-origin rhesus macaques, infected with simian immunodeficiency virus (SIV) are important animal models that emulate key features of HIV-1 infection, including high viral loads ( 16 ), progressive CD4 + T cell depletion ( 17 – 19 ), envelope protein (Env) trafficking and evolution ( 20 , 21 ), response to ART ( 16 , 22 – 24 ), and establishment of a latent reservoir in resting CD4 + T cells ( 25 – 27 ). Although studies of NHPs infected with various forms of SIV have aided in the analysis of cure strategies, structural differences between the SIV and HIV-1 Env proteins restrict application of this model in studies of interventions targeting HIV-1 Env.…”