In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 18, No. 4 ( 2022-4-4), p. e1010416-
Abstract:
We investigated the impact of monocytes, NK cells, and CD8 + T-cells in primary HTLV-1 infection by depleting cell subsets and exposing macaques to either HTLV-1 wild type (HTLV-1 WT ) or to the HTLV-1 p12KO mutant unable to infect replete animals due to a single point mutation in orf-I that inhibits its expression. The orf- I encoded p8/p12 proteins counteract cytotoxic NK and CD8 + T-cells and favor viral DNA persistence in monocytes. Double NK and CD8 + T-cells or CD8 depletion alone accelerated seroconversion in all animals exposed to HTLV-1 WT . In contrast, HTLV-1 p12KO infectivity was fully restored only when NK cells were also depleted, demonstrating a critical role of NK cells in primary infection. Monocyte/macrophage depletion resulted in accelerated seroconversion in all animals exposed to HTLV-1 WT , but antibody titers to the virus were low and not sustained. Seroconversion did not occur in most animals exposed to HTLV-1 p12KO. In vitro experiments in human primary monocytes or THP-1 cells comparing HTLV-1 WT and HTLV-1 p12KO demonstrated that orf-I expression is associated with inhibition of inflammasome activation in primary cells, with increased CD47 “don’t-eat-me” signal surface expression in virus infected cells and decreased monocyte engulfment of infected cells. Collectively, our data demonstrate a critical role for innate NK cells in primary infection and suggest a dual role of monocytes in primary infection. On one hand, orf-I expression increases the chances of viral transmission by sparing infected cells from efferocytosis, and on the other may protect the engulfed infected cells by modulating inflammasome activation. These data also suggest that, once infection is established, the stoichiometry of orf-I expression may contribute to the chronic inflammation observed in HTLV-1 infection by modulating monocyte efferocytosis.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1010416
DOI:
10.1371/journal.ppat.1010416.g001
DOI:
10.1371/journal.ppat.1010416.g002
DOI:
10.1371/journal.ppat.1010416.g003
DOI:
10.1371/journal.ppat.1010416.g004
DOI:
10.1371/journal.ppat.1010416.g005
DOI:
10.1371/journal.ppat.1010416.g006
DOI:
10.1371/journal.ppat.1010416.t001
DOI:
10.1371/journal.ppat.1010416.t002
DOI:
10.1371/journal.ppat.1010416.s001
DOI:
10.1371/journal.ppat.1010416.s002
DOI:
10.1371/journal.ppat.1010416.s003
DOI:
10.1371/journal.ppat.1010416.s004
DOI:
10.1371/journal.ppat.1010416.s005
DOI:
10.1371/journal.ppat.1010416.s006
DOI:
10.1371/journal.ppat.1010416.s007
DOI:
10.1371/journal.ppat.1010416.s008
DOI:
10.1371/journal.ppat.1010416.s009
DOI:
10.1371/journal.ppat.1010416.s010
DOI:
10.1371/journal.ppat.1010416.s011
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2205412-1
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