The Envelope Cytoplasmic Tail of HIV-1 Subtype C Contributes to Poor Replication Capacity through Low Viral Infectivity and Cell-to-Cell Transmission

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.

Subtype C HIV-1 reservoirs throughout the body in ART-suppressed individuals

“…In addition, mice with severe combined immunodeficiency (SCID) injected with subtype C HIV-1–infected macrophages exhibited less cognitive deficits and brain pathology than those infected with subtype B HIV-1 ( 57 ). Furthermore, subtype C HIV-1 was found to have slower replication kinetics in monocyte-derived macrophages, resulting in lower levels of macrophage-mediated neurotoxicity in vitro ( 58 ). These investigations suggest subtype C HIV-1 differentially accesses the CNS parenchyma in comparison with subtype B, indicating that the brain is an unfavorable or inaccessible reservoir site for subtype C HIV-1.…”

Why Are Some HIV-1 Subtypes More “Wimpy” at Causing Disease?

“…It has been proposed that a smaller V1V2 region with less glycosylation can enhance HIV-1 fusion for subtype C viruses on both CD4 T-cells and macrophage [9]. A more recent study has indicated that genetic variations within the subtype C gp41 molecule can impede HIV-1 entry and replication within CD4 T-cells and modulate cell-to-cell transmission but not in macrophages [10]. The results are interpreted that subtype specific Env incorporation within viral membranes can be subtype specific.…”