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+ Tcells,
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.
