Phenotypic characterisation of Human Immunodeficiency Virus type 1 Envelope entry efficiency of transmitted/founder variants circulating in Mbeya, Tanzania

Abstract

Background: Altered fitness of transmitted founder (T/F) HIV-1 variants has been linked to slowed disease progression, yet almost all of these studies have focussed on the role of attenuating immune escape mutations in T/F Gag or entry efficiency of Envelope (Env) in long-term non-progressors (LTNP) and elite suppressors (ES) during chronic stages of infection. As Env could also play an important role in viral fitness during early infection, we investigated if T/F Env entry efficiency, prior to immune selection, affected viral loads of progressors in vivo. Findings: Functional Env clones from eight progressors and one LTNP, representing the T/F virus responsible for clinical infection, were constructed. Subsequently Env pseudoviruses (PSVs) were generated, and confirmed to be all R5 but not macrophage tropic. PSVs had a ~80 fold range in entry efficiencies using TZM-bl cells with the LTNP being the poorest enterer. Enhanced entry was associated with increased viral load at 3 months although this association was reduced by 12 months. Finally, we show that entry efficiency was influenced by fusion capacity, CCR5/CD4 dependency, and/or incorporation of gp120 into pseudovirions.Conclusion: The variation in TZM-bl entry efficiency of T/F viruses was due to one or more advantageous Env attributes. Viruses with high entry efficiency may have a replication advantage subsequent to transmission, leading to increased viral loads during early infection of progressors.