Figure 3.

Scheme illustrating the events associated with tubulin cytoskeleton reorganization and modification that underlie HIV-1 Env function to drive pore fusion formation, viral entry, and infection. (A) Functional HIV-1 Envs (P, RP and VNP) signal through CD4 to stabilize MTs by acetylation. Acetylated MTs project to the virus–cell contact regions near the plasma membrane in AFs-associated pseudopods, facilitating HIV-1 Env (gp41) fusion activity and viral entry. This HIV-1-mediated MTs reorganization and PTM are under the control of HDAC6 tubulin-deacetylase and the HDAC6/TARDBP (TDP-43) axis, which inhibit viral infection. Notably, functional HIV-1 Envs from viruses of patients with viremic and progressors clinical outcomes overcome the antiviral activity of the tubulin-deacetylase HDAC6 (i.e., the HDAC6/TARDBP axis), thereby stabilizing MTs to productively infect cells. In contrast, deficient HIV-1 Envs from LTNP-EC individuals could not acetylate MTs and were not capable of infecting cells. Once the viral core enters the cell, it uses stable MTs, associated adaptors, and molecular motors to travel to the nuclear envelope, such as dynein and BICD2 (control of HIV-1 capsid transport direction and speed), Dia1/Dia2 (stabilize MTs by acting on the EB1-kif4 pathway to facilitate perinuclear trafficking), FEZ1 (associates viral core with kinesin-1 to reach the nucleus following tubulin tracks), and/or CLASP2 (EB1-associated +TIPs protein that stabilizes MTs and recruits viral core). In the nuclear envelope, HIV-1 capsid interacts with nucleoporins associated with NPCs to translocate into the nucleus. (B) Functional HIV-1 Envs from P, RP, and VNP patients trigger MT acetylation in a CD4-dependent manner to promote pore fusion and evade the antiviral action of endogenous tubulin-deacetylase HDAC6, which is under the control of TARDBP (TDP-43). These functional Envs could also promote late autophagy by long-lasting contact with CD4, which provokes cell death in noninfected bystander cells. In this sense, HIV-1 Envs from viruses of LTNP-EC individuals are insufficient to form the fusion pore and infect due to their inability to escape the tubulin-deacetylase barrier. Notably, viral particles bearing EC-Envs gain infection function when HDAC6 or the HDAC6/TARDBP axis is inhibited by either using HDAC6 inhibitors or its nonactive mutants or interfering with HDAC6/TARDBP mRNA, thereby stabilizing MTs to generate a cell permissive state for infection. Designs and templates were created with BioRender.