Monocytes and macrophages are part of innate immunity and constitute the first line of defense against pathogens. Bone marrow-derived monocytes circulate in the bloodstream for one to three days and then typically migrate into tissues, where they differentiate into macrophages. Circulatory monocytes represent 5% of the nucleated cells in normal adult blood. Following differentiation, macrophages are distributed into various tissues and organs to take residence and maintain body homeostasis. Emerging evidence has highlighted the critical role of monocytes/macrophages in oncogenic viral infections, mainly their crucial functions in viral persistence and disease progression. These findings open opportunities to target innate immunity in the context of oncogenic viruses and to explore their potential as immunotherapies.

The human T-cell leukemia type-1 (HTLV-1) retrovirus establishes chronic life-long infection in a fraction of infected individuals associated with severe pathological conditions. Although the mechanism driving disease development is not fully understood, current evidence indicates the essential functions of viral regulatory proteins. Among these, the p13 protein has previously been shown to localize to the inner mitochondrial membrane in T cells, altering mitochondrial biology and T-cell function. While CD4⁺ T cells are the primary cell target of HTLV-1 infection, genomic viral DNA has also been detected in monocytes, macrophages, and dendritic cells, which orchestrate innate and adaptive immunity and play a critical role in protecting against virus-induce diseases by establishing the appropriate balance of pro and anti-inflammatory responses. Given the central role of mitochondria in monocyte differentiation, we investigated the effect of p13 in monocytes/macrophages and found that by localizing to mitochondria, p13 affects mitochondrial respiration. Moreover, we demonstrate that p13 expression affects macrophage polarization to favor the recruitment of CD4⁺ T cells, the primary target of the virus, potentially facilitating the spread of viral infection and the development of disease.

Exposure to Bacillus Calmette-Guérin (BCG) or Canarypox ALVAC/Alum vaccine elicits pro- or antiinflammatory innate responses, respectively. We tested whether prior exposure of macaques to these immunogens protected against SARS-CoV-2 replication in lungs and found more efficient replication control after the pro-inflammatory immunity elicited by BCG. The decreased virus level in lungs was linked to early infiltrates of classical monocytes producing IL-8 with systemic neutrophils, Th2 cells, and Ki67 ⁺ CD95 ⁺ CD4 ⁺ T cells producing CCR7. At the time of SARS-CoV-2 exposure, BCG-treated animals had higher frequencies of lung infiltrating neutrophils and higher CD14 ⁺ cells expressing efferocytosis marker MERTK, responses correlating with decreased SARS-CoV-2 replication in lung. At the same time point, plasma IL-18, TNF-α, TNFSF-10, and VEGFA levels were also higher in the BCG group and correlated with decreased virus replication. Finally, after SARS-CoV-2 exposure, decreased virus replication correlated with neutrophils producing IL-10 and CCR7 preferentially recruited to the lungs of BCG-vaccinated animals. These data point to the importance of the spatiotemporal distribution of functional monocytes and neutrophils in controlling SARS-CoV-2 levels and suggest a central role of monocyte efferocytosis in curbing replication.