Modulation of Human Immunodeficiency Virus Type 1 Infectivity through Incorporation of Tetraspanin Proteins

Abstract

Accumulating evidence indicates that human immunodeficiency virus type 1 (HIV-1) acquires various cellular membrane proteins in the lipid bilayer of the viral envelope membrane. Although some virionincorporated cellular membrane proteins are known to potently affect HIV-1 infectivity, the virological functions of most virion-incorporated membrane proteins remain unclear. Among these host proteins, we found that CD63 was eliminated from the plasma membranes of HIV-1-producing T cells after activation, followed by a decrease in the amount of virion-incorporated CD63, and in contrast, an increase in the infectivity of the released virions. On the other hand, we found that CD63 at the cell surface was preferentially embedded on the membrane of released virions in an HIV-1 envelope protein (Env)-independent manner and that virionincorporated CD63 had the potential to inhibit HIV-1 Env-mediated infection in a strain-specific manner at the postattachment entry step(s). In addition, these behaviors were commonly observed in other tetraspanin proteins, such as CD9, CD81, CD82, and CD231. However, L6 protein, whose topology is similar to that of tetraspanins but which does not belong to the tetraspanin superfamily, did not have the potential to prevent HIV-1 infection, despite its successful incorporation into the released particles. Taken together, these results suggest that tetraspanin proteins have the unique potential to modulate HIV-1 infectivity through incorporation into released HIV-1 particles, and our findings may provide a clue to undiscovered aspects of HIV-1 entry.

Extracellular vesicles and viruses: Are they close relatives?

“…A number of cellular proteins are incorporated both in EVs and in virions. Tetraspanins, for example, are associated with EVs and have also been reported to be incorporated into retroviruses, in which these host proteins can play a role in infectivity (26). Other EV membrane proteins can act as ligands for receptors on the target cell plasma membrane.…”

Tetraspanins at a glance

“…Several tetraspanins are recruited to the budding site of HIV (Krementsov et al, 2010) and are incorporated into the viral membrane (Monk and Partridge, 2012). Furthermore, the presence of tetraspanins at exit sites and in viral particles inhibits, to some extent, virus infection at a post-attachment step, as well as the formation of syncytium induced by the virus (Gordón-Alonso et al, 2006;Krementsov et al, 2009;Sato et al, 2008). Takeda et al, 2007).…”

Vpu Augments the Initial Burst Phase of HIV-1 Propagation and Downregulates BST2 and CD4 in Humanized Mice

“…293T cells, HeLa cells, HEK293 cells, and TZM-bl cells (obtained through the NIH AIDS Research and Reference Reagent Program) (70) were maintained in Dulbecco's modified Eagle medium (DMEM) containing 10% fetal calf serum, 100 U/ml penicillin, and 100 g/ml streptomycin as previously described (27,51,52,56). Primary human CD4 ϩ T cells were isolated from the peripheral blood of a healthy donor by using a human CD4 ϩ T cell isolation kit (Miltenyi) according to the manufacturer's protocol.…”