Analysis of HIV-1-X4 Fusion with Immature Dendritic Cells Identifies a Specific Restriction that Is Independent of CXCR4 Levels

Abstract

Immature dendritic cells (iDCs) are likely to be among the first targets of HIV infection during sexual transmission. We analyzed whether the relatively inefficient viral replication in iDCs could be attributed to specific restrictions during the viral life cycle. Using iDCs from a panel of donors, we set out to compare their capacity to support infection and propagation of X4- and R5-tropic viruses. We also performed quantitative flow cytometry to determine levels of relevant cell-surface CD4 and HIV-1 co-receptors. Although iDCs express comparable levels of functional CXC chemokine receptor 4 (CXCR4) and CC chemokine receptor 5 (CCR5) at the cell surface, they are 100- to 1,000-fold less susceptible to infection by X4- versus R5-tropic HIV-1 strains. Increasing surface expression of CXCR4 by transduction with lentiviral vectors did not lead to increased replication of the X4-tropic strains. Fusion of HIV-X4 with iDCs was markedly less efficient compared to that of HIV-R5. We conclude that an env-specific block early in the viral cycle operates in iDCs. This restriction may play a role in the exclusion of X4-tropic strains during HIV-1 transmission.

Identification of an Arsenic-Sensitive Block to Primate Lentiviral Infection of Human Dendritic Cells

“…Remarkably, As 2 O 3 treatment increased the percentage of HIV-infected DC by up to 50-fold, depending on the virus strain. As iDC express a relatively low quantity of HIV coreceptors in comparison to CD4 ϩ T cells (25), we verified that As 2 O 3 treatment did not result in the alteration of HIV receptor or coreceptor levels by quantitative fluorescence-activated cell sorter (FACS) analysis of iDC as described previously (25). Modest changes in receptor and coreceptor levels induced by As 2 O 3 could not explain the strong stimulation of HIV replication (data not shown).…”

“…In the absence of viral replication, DC, including Langerhans cells, can capture and transfer HIV type 1 (HIV-1) to CD4 ϩ T cells via an infectious synapse, which results in high levels of infection (1,13,20,37). There is an early block to HIV-1 entry into DC (6,9,25), as well as a strong postentry block to infection (26). The TRIM5 and APOBEC families have recently been shown to be able to block retroviral infection in primate cells (31,35), as reviewed in references 5, 23, and 32.…”

“…iDC were generated by 6-day culture of monocytes in a mixture of granulocyte-macrophage colony-stimulating factor and interleukin-4 as described previously (8,26). The iDC were then pretreated with As 2 O 3 (2 M) for 18 h, and groups of iDC were infected in parallel with a variety of HIV-1 strains using either CXCR4 or CCR5 coreceptors, as described previously (25) (Fig. 1).…”

CD134 and CXCR4 expression corresponds to feline immunodeficiency virus infection of lymphocytes, macrophages and dendritic cells

“…HIV, a lymphotropic lentivirus like FIV, is captured by lectin receptors on DCs at mucosal surfaces, translocated to specific cytoplasmic organelles and subsequently transmitted to CD4 + lymphocytes in lymph nodes (Lekkerkerker et al, 2006). In addition, HIV enters DCs through CD4 and chemokine receptor interactions, with genomic integration and full replication modulated by the maturational stage of DCs (Pion et al, 2007). The nature of different DC populations in cats, the only nonprimate naturally susceptible to lymphotropic lentiviruses, has not been elucidated fully.…”

Coreceptors and HIV-1 Pathogenesis

“…HIV-1 escapes this degradation process in DC via mechanisms involving HIV-1-mediated inhibition of autophagy [48•]. DC express both CCR5 and CXCR4 and contribute to HIV-1 replication in cis [49]. DC permissiveness to R5 HIV-1 entry is significantly higher compared to X4 HIV-1 strains, despite high levels of CXCR4 expression [49].…”