The HIV Reservoir in Monocytes and Macrophages

Abstract

In people living with HIV (PLWH) who are failing or unable to access combination antiretroviral therapy (cART), monocytes and macrophages are important drivers of pathogenesis and progression to AIDS. The relevance of the monocyte/macrophage reservoir in PLWH receiving cART is debatable as in vivo evidence for infected cells is limited and suggests the reservoir is small. Macrophages were assumed to have a moderate life span and lack self-renewing potential, but recent discoveries challenge this dogma and suggest a potentially important role of these cells as long-lived HIV reservoirs. This, combined with new HIV infection animal models, has led to a resurgence of interest in monocyte/macrophage reservoirs. Infection of non-human primates with myeloid-tropic SIV implicates monocyte/macrophage activation and infection in the brain with neurocognitive disorders, and infection of myeloid-only humanized mouse models are consistent with the potential of the monocyte/macrophage reservoir to sustain infection and be a source of rebound viremia following cART cessation. An increased resistance to HIV-induced cytopathic effects and a reduced susceptibility to some antiretroviral drugs implies macrophages may be relevant to residual replication under cART and to rebound viremia. With a reappraisal of monocyte circulation dynamics, and the development of techniques to differentiate between self-renewing tissue-resident, and monocyte-derived macrophages in different tissues, a new framework exists to contextualize and evaluate the significance and relevance of the monocyte/macrophage HIV reservoir. In this review, we discuss recent developments in monocyte and macrophage biology and appraise current and emerging techniques to quantify the reservoir. We discuss how this knowledge influences our evaluation of the myeloid HIV reservoir, the implications for HIV pathogenesis in both viremic and virologically-suppressed PLWH and the need to address the myeloid reservoir in future treatment and cure strategies.

Moving beyond the mousetrap: current and emerging humanized mouse and rat models for investigating prevention and cure strategies against HIV infection and associated pathologies

“…The human spleen in the BLTS-humanized mouse model recapitulates human adult spleen architecture and facilitates better reconstitution of immune cells, including human red pulp macrophages, which are poorly reconstituted in the BLT-humanized mouse model [5]. It is well established that macrophages can serve as a reservoir for HIV [106][107][108]; thus, the BLTS-humanized mouse model provides a system for investigating human splenic macrophage-HIV interactions [5]. Additionally, the spleen is a major lymphoid tissue reservoir, with B cell follicles in the white-pulp serving as an immune privilege site for anti-HIV T-cells [109].…”

Diversity of small molecule HIV‐1 latency reversing agents identified in low‐ and high‐throughput small molecule screens

“…Additionally, we note that most of the small molecule screens for novel LRAs (Table ), except for two small scale studies, were performed using T‐cell lines or primary cells, and there has not yet been significant effort toward identifying LRAs that may be specifically effective in monocyte‐macrophage lineages. Because these cell types represent important reservoirs for virus in patients on ART, it may be necessary to target unique aspects of provirus regulation in these cells.…”

Apoptosis characterization in mononuclear blood leukocytes of HIV patients during dengue acute disease

“…CD14 ++ CD16 − classical monocytes presented high phagocytic activity and they are critical for initial inflammatory responses while CD14 ++ CD16 + intermediate monocytes are associated with inflammatory response, and CD14 + CD16 ++ non-classical are considered as patrolling monocytes 21 . Monocyte activation has been reported during DENV and HIV infections and they are associated with disease pathogenesis 22,40 . Our results demonstrated significant changes of monocyte subsets during DENV and DENV/HIV coinfection.…”