A Cellular Restriction Dictates the Permissivity of Nondividing Monocytes/Macrophages to Lentivirus and Gammaretrovirus Infection

Abstract

SUMMARY Primate lentiviruses including HIV-1 have evolved the capacity to transduce terminally differentiated, non-dividing myeloid cells and as a consequence, these viruses establish persistent infections of tissue macrophage and microglia in the host. In contrast, non-dividing myeloid cells are refractory to infection by gammaretroviruses such as MLV. Here we present evidence that a cellular restriction is the obstacle to transduction of macrophage by MLV. Neutralization of the restriction by Vpx, a primate lentiviral protein previously shown to protect primate lentiviruses from a macrophage restriction, rendered macrophage permissive to MLV infection. Packaging of Vpx within MLV virions was sufficient to confer a lentivirus phenotype for MLV. We further demonstrate that this restriction prevents transduction of quiescent monocytes by HIV-1. Monocyte- HeLa heterokaryons were resistant to HIV-1 infection while heterokaryons formed between monocytes and HeLa cells expressing Vpx were permissive to HIV-1 infection. Encapsidation of Vpx within HIV-1 virions conferred the ability to infect quiescent monocytes. Collectively our results indicate that the relative ability of lentiviruses and gammaretroviruses to transduce non-dividing, myeloid-cells is dependent upon their ability to neutralize a cellular restriction and that this restriction shapes the association of lentiviruses with myeloid cell reservoirs in the host.

How Samhd1 changes our view of viral restriction

“…Similarly, BST-2 is promiscuous in its ability to counteract enveloped viruses [64,65]. Interestingly, restriction of murine leukemia virus at the reverse transcription step is abrogated by Vpx in monocytes and macrophages [66,67], suggesting that SAMHD1 may exert its restriction activity against viruses other than lentiviruses. Additionally, if the deoxynucleotide triphosphohydrolase activity is found to be involved in SAMHD1-mediated HIV restriction, then SAMHD1 would be expected to act as restriction factor of viruses that require DNA synthesis during their life cycle.…”

SAMHD1 Restricts HIV-1 Cell-to-Cell Transmission and Limits Immune Detection in Monocyte-Derived Dendritic Cells

“…Vpx facilitates replication of HIV-2 and some SIV in myeloid cells but is dispensable in cycling lymphocytes (4). Vpx triggers the destruction of an early-acting restriction factor and promotes synthesis of viral DNA in nondividing cells (6). This restriction factor is active against not only HIV-2 and SIV but also retroviruses like HIV-1 that lack Vpx.…”

“…APOBEC proteins induce G-to-A hypermutations in the nascent viral DNA during reverse transcription, while tetherin blocks viral release (2). Other primate lentiviruses (human immunodeficiency virus type 2 [HIV-2] and simian immunodeficiency virus [SIV]) possess an additional protein, Vpx, whose function has recently been deciphered (4)(5)(6)(7)(8). Vpx facilitates replication of HIV-2 and some SIV in myeloid cells but is dispensable in cycling lymphocytes (4).…”

“…However, intracellular delivery of Vpx to MDDCs, through treatment with nonreplicative SIV particles carrying Vpx, dramatically enhances HIV-1 infection (6,9). Vpx acts by inducing the nuclear degradation of SAMHD1, a cellular protein found in various cell types, including myeloid cells (5,7,10,11) and CD4 ϩ T lymphocytes (12)(13)(14)(15).…”

SAMHD1— A HIV-1 restriction factor derived from myeloid lineage monocytes

“…HIV-1 感染的因子, 并且这种限制性作用能被 Vpx 所抵消 (Goujon et al, 2007(Goujon et al, , 2008Hirsch et al, 1998;Kaushik et al, 2009;Sharova et al, 2008) (Lim et al, 2012;Tristem et al, 1992) …”