An Envelope-Determined, pH-Independent Endocytic Route of Viral Entry Determines the Susceptibility of Human Immunodeficiency Virus Type 1 (HIV-1) and HIV-2 to Lv2 Restriction

Abstract

We identified a postentry restriction, termed Lv2, which determines the cellular tropism of two related human immunodeficiency virus type 2 (HIV-2) isolates and is dependent on the sequence of the capsid (CA) and envelope (Env) proteins. To explain the reliance on both CA and Env, we proposed that restrictive Envs deliver susceptible capsids to a compartment where Lv2 is active whereas nonrestrictive Envs deliver capsids into a compartment where Lv2 is either absent or less active. To test this model, we used compounds that affect endocytic pathways (ammonium chloride, bafilomycin A1, hypertonic sucrose) or lipid rafts (methyl-␤-cyclodextrin) to treat restrictive cells and show that restricted virus can be rescued from Lv2 if a lipid-raftdependent, pH-independent endocytic pathway is inhibited. Furthermore, viral entry into HeLa/CD4 cells containing a tailless CD4 receptor, located outside lipid rafts, was fully permissive. Finally, we show that a variety of primary HIV-1 and HIV-2 viruses are susceptible to Lv2. Thus, we show that the route of entry, determined by the viral envelope, can influence cellular tropism by avoiding intracellular blocks to infection.

Predominant Mode of Human Immunodeficiency Virus Transfer between T Cells Is Mediated by Sustained Env-Dependent Neutralization-Resistant Virological Synapses

“…6) (W. Hübner and B. K. Chen, unpublished data) suggest that the virus is translocated into an internal compartment in the (12,16,17,35,57). Because studies of endocytic pathways of viral internalization largely have been performed with cell-free virus, we now must consider that transfer of virus into cells by VS may drive HIV into endocytic routes at levels that are orders of magnitude higher than previously appreciated.…”

Cytoplasmic Body Component TRIM5α Requires Lipid-enriched Microdomains for Efficient HIV-1 Restriction

“…Involvement of cellular lipids in the post-entry restriction of HIV has been reported as Lv2 activity, where a yet-to-be-identified restriction factor determines the cellular tropism of two related HIV type 2 (HIV-2) isolates (66 -68). Lv2 restriction is determined by the viral capsid and envelope protein sequences, and Lv2 lentiviral restriction activity is determined by the route of viral entry; the restriction is only prominent after the restriction-sensitive viral core reached a subcellular compartment where Lv2 activity is accessible (67,68). Although Lv2 restriction appears to be independent of human TRIM5␣-mediated post-entry restriction (66), these observations indicate the involvement of cellular lipids in the post-entry restriction of lentiviruses.…”

Tissue-specific restriction of cyclophilin A-independent HIV-1- and SIV-derived lentiviral vectors

“…Tissue-specific restriction of lentiviral vectors CA Kahl et al VSV-G can bypass the Lv2 and Lv3 restrictions, 12,13,26 whereas the present infectivity block was observed with VSV-G-pseudotyped lentiviral vectors. Emerging reports also postulate the existence of another restriction factor(s) in human cells that is different from TRIM5a Hu , but that is modulated by CypA.…”