Abstract
The cytoplasmic tail (gp41CT) of the HIV-1 envelope (Env) mediates Env incorporation into virions and regulates Env intracellular trafficking. Little is known about the functional impact of variability in this domain. To address this issue, we compared the replication of recombinant virus pairs carrying the full Env (Env viruses) or the Env ectodomain fused to the gp41CT of NL4.3 (EnvEC viruses) (12 subtype C and 10 subtype B pairs) in primary CD4+ T-cells and monocyte-derived-macrophages (MDMs). In CD4+ T-cells, replication was as follows: B-EnvEC = B-Env>C-EnvEC>C-Env, indicating that the gp41CT of subtype C contributes to the low replicative capacity of this subtype. In MDMs, in contrast, replication capacity was comparable for all viruses regardless of subtype and of gp41CT. In CD4+ T-cells, viral entry, viral release and viral gene expression were similar. However, infectivity of free virions and cell-to-cell transmission of C-Env viruses released by CD4+ T-cells was lower, suggestive of lower Env incorporation into virions. Subtype C matrix only minimally rescued viral replication and failed to restore infectivity of free viruses and cell-to-cell transmission. Taken together, these results show that polymorphisms in the gp41CT contribute to viral replication capacity and suggest that the number of Env spikes per virion may vary across subtypes. These findings should be taken into consideration in the design of vaccines.
Highlights
Spread of Human Immunodeficiency Virus (HIV-1) to new target cells in vitro and in vivo occurs via infection with free virions or by direct transmission of newly synthesized virions budding from an infected “donor” cell to a nearby target cell [1,2,3,4,5,6,7,8] reviewed in [9, 10]
To assess whether naturally occurring polymorphisms in the gp41CT impact viral replication, we used a comparative approach based on NL4.3-derived paired recombinant viruses containing patient-derived sequences spanning the full env or the env ectodomain and transmembrane domain (Fig 1)
Replication of viruses with subtype C gp41CT plateaued after day 5 and the difference in viral replication was amplified over time, suggestive of hindered propagative infection
Summary
Spread of Human Immunodeficiency Virus (HIV-1) to new target cells in vitro and in vivo occurs via infection with free virions or by direct transmission of newly synthesized virions budding from an infected “donor” cell to a nearby target cell [1,2,3,4,5,6,7,8] reviewed in [9, 10]. The surface subunit gp120 ensures viral adsorption and binding to the CD4 receptor [14,15,16] and the coreceptor (CCR5 or CXCR4) [17,18,19,20] These interactions induce a series of conformational changes in Env and lead to the insertion of the fusion peptide located at the N-terminus of the transmembrane subunit gp into the target cell membrane and to fusion of the viral and cellular membranes [21,22,23,24,25,26,27]. The Env surface subunit gp120 and the extracellular portion of gp have been extensively studied, but the cytoplasmic domain of Env (gp41CT) has been granted far less attention and many of its functions remain poorly understood or speculative
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