NK cells and monocytes modulate primary HTLV-1 infection

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. Author summaryThe immune cells that inhibit or favor HTLV-1 infection are still unknown and their identification is critical for understanding viral pathogenesis and for the development of an effective HTLV-1 vaccine. Neutralizing antibodies are produced in natural HTLV-1 infection, but their impact is likely hampered by the virus's ability to be transmitted from cell to cell via the virological synapse, cellular conduits, and biofilms. By depleting specific immune cell subsets in blood, we found that NK cells play a critical role in the containment of early HTLV-1 infection. Moreover, transient depletion of monocytes/macrophages results in early, but not sustained seroconversion, suggesting that early engagement of monocytes may be necessary for long-term productive infection. The engulfment of apoptotic T-cells infected by HTLV-1 may represent a viral strategy to persist in the host since the viral proteins encoded by orf-I and orf-II affect the function of receptors and proteins involved in efferocytosis. These results suggest that effective HTLV-1 vaccines must also elicit durable innate responses able to promptly clear virus invasion of monocytes through engulfment of infected T-cells to avoid the establishment of a vicious cycle that leads to chronic inflammation.