Myeloid Cells Enriched for a Dendritic Cell Population From People Living With HIV Have Altered Gene Expression Not Restored by Antiretroviral Therapy

Abstract

Antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infections has been designed to optimize CD4 T-cell survival and limit HIV replication. Cell types other than CD4 T cells such as monocytes/macrophage, dendritic cells, and granulocytes (collectively known as myeloid cells), are generally not considered in the development of ART protocols. Myeloid dendritic cells (mDCs) are the most potent inducers of CD4 T-cell activation and central to the regulation of immune responses. mDCs in the blood are decreased in number, altered in function, and implicated in promoting HIV latency in people living with HIV (PLWH). We found that cells enriched for mDC in PLWH had transcriptional changes compared to mDC from HIV uninfected individuals, some of which were not completely restored by ART. In contrast, other mDC functions such as interleukin-1 signaling and type I interferon pathways were restored by ART. Some of the transcriptional changes in mDC not completely reversed by ART were enriched in genes that are classically associated with cells of the monocyte/macrophage lineage, but new single-cell RNA sequencing studies show that they are also expressed by a subset of mDC. A cellular enzyme, acyloxyacyl hydrolase (AOAH), important for lipopolysaccharide (LPS) detoxification, had increased transcription in mDC of PLWH, not restored by ART. It is possible that one reason ART is not completely successful in PLWH is the failure to phenotypically change the mDCs. Thus, inability of ART to be completely effective might involve myeloid cells and the failure to restore mDC function as measured by gene transcription. We suggest that mDC and myeloid cells should be considered in future combination ART development.

The Role of Dendritic Cells During Infections Caused by Highly Prevalent Viruses

“…Studies in vitro with human DCs have demonstrated that some of these cells are susceptible to the infection with HIV, such as Langerhans cells, cDCs, and pDCs (253,254). Interestedly, cDCs from HIV patients have shown low levels in the blood, and their function is compromised (255). When HIV infects DCs, it can travel within the cell until it locates memory CD4 + T cells into the lymphoid tissue, spreading the infection in this way (256,257).…”

“…Upon the HIV-infection of cDCs, the anti-viral pathways within these cells are changed, and as a result, it promotes the viral spreading. However, the use of antiretroviral therapies (ART) can return completely the functionality of the pathways IL-1 and type I IFN (255,259).…”

Biochemical transformation of bacterial lipopolysaccharides by acyloxyacyl hydrolase reduces host injury and promotes recovery

“…Although AOAH was intially found in neutrophils (9), cellular levels of AOAH are often lower in circulating and exudate neutrophils than in monocytes/macrophages, hepatic Kupffer cells (56), immature dendritic cells (57,58), and NK cells. AOAH expression has also been found in mucosal ILC1 cells, which are closely related to NK cells but lack granulysin and perforin and have a genomic 'superenhancer' region that includes part of the AOAH gene (59).…”

Persistent T Cell Repertoire Perturbation and T Cell Activation in HIV After Long Term Treatment

“…Some of this is attributed to exposures such as tobacco smoking (7,8) and ART-related toxicity (9), but predictors of clinical outcome in this context also include circulating markers of inflammation such as pro-inflammatory cytokines (IL6), acute phase proteins (CRP, fibrinogen) and markers of leukocyte activation (soluble CD14 and CD163), suggesting persistent immune dysregulation in PLHIV despite effective ART (10,11). Enrichment of pro-inflammatory states has also been reflected in transcriptional studies of blood monocytes (12), myeloid dendritic cells (13) and CD4 T cells (14) from ART-treated PLHIV. The immunological pathways that underpin these observations are not fully understood.…”