Abstract
CD4 and chemokine receptors mediate HIV-1 attachment and entry. They are, however, insufficient to explain the preferential viral infection of central memory T cells. Here, we identify L-selectin (CD62L) as a viral adhesion receptor on CD4+ T cells. The binding of viral envelope glycans to L-selectin facilitates HIV entry and infection, and L-selectin expression on central memory CD4+ T cells supports their preferential infection by HIV. Upon infection, the virus downregulates L-selectin expression through shedding, resulting in an apparent loss of central memory CD4+ T cells. Infected effector memory CD4+ T cells, however, remain competent in cytokine production. Surprisingly, inhibition of L-selectin shedding markedly reduces HIV-1 infection and suppresses viral release, suggesting that L-selectin shedding is required for HIV-1 release. These findings highlight a critical role for cell surface sheddase in HIV-1 pathogenesis and reveal new antiretroviral strategies based on small molecular inhibitors targeted at metalloproteinases for viral release.
Highlights
CD4 and chemokine receptors mediate Human immunodeficiency virus type 1 (HIV-1) attachment and entry
While glycosylations on gp[120] shields the virus from humoral immune recognition[4,5], the viral glycans are often recognized by host lectin receptors, such as mannose receptor (MR), DEC-205, and DC-SIGN on macrophage and dendritic cells leading to viral capture and antigen presentation[6,7,8,9]
As L-selectin is expressed on CD4+ T cells and partially colocalized with CD4 (Supplementary Figures 2E–2H), we incubated gp120-Qdots with CD4+ human peripheral blood mononuclear cells (PBMC) in the presence of CD4 or L-selectin blocking antibodies
Summary
CD4 and chemokine receptors mediate HIV-1 attachment and entry. They are, insufficient to explain the preferential viral infection of central memory T cells. As L-selectin is expressed on both CD4+ and CD8+ T cells, we examined the binding of HIV-1BAL virus to CD62L-sorted CD8+ T cells from PBMC to avoid the involvement of CD4 (Supplementary Figure 3A). The infections of CD62L-CEM #2 and #25 by a replication-competent X4-tropic HIVLAI were 3-to-4-fold higher than that of the parental CEM cells as measured by intracellular viral capsid p24 staining (Fig. 2a), suggesting that L-selectin facilitated HIV-1 infection.
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