Retroviruses As Myeloid Cell Riders: What Natural Human Siglec-1 "Knockouts" Tell Us About Pathogenesis

Abstract

Myeloid cells initiate immune responses and are crucial to control infections. In the case of retroviruses, however, myeloid cells also promote pathogenesis by enabling viral dissemination; a process extensively studied in vitro using human immunodeficiency virus type 1 (HIV-1). This viral hijacking mechanism does not rely on productive myeloid cell infection but requires HIV-1 capture via Siglec-1/CD169, a receptor expressed on myeloid cells that facilitates the infection of bystander target cells. Murine retroviruses are also recognized by Siglec-1, and this interaction is required for robust retroviral infection in vivo. Yet, the relative contribution of Siglec-1-mediated viral dissemination to HIV-1 disease progression remains unclear. The identification of human null individuals lacking working copies of a particular gene enables studying how this loss affects disease progression. Moreover, it can reveal novel antiviral targets whose blockade might be therapeutically effective and safe, since finding null individuals in natura uncovers dispensable functions. We previously described a loss-of-function variant in SIGLEC-1. Analysis of a large cohort of HIV-1-infected individuals identified homozygous and heterozygous subjects, whose cells were functionally null or partially defective for Siglec-1 activity in HIV-1 capture and transmission ex vivo. Nonetheless, analysis of the effect of Siglec-1 truncation on progression to AIDS was not conclusive due to the limited cohort size, the lack of complete clinical records, and the restriction to study only off-therapy periods. Here, we review how the study of loss-of-function variants might serve to illuminate the role of myeloid cells in viral pathogenesis in vivo and the challenges ahead.

Keywords: Siglec-1; antigen-presenting cell; genome; human; human immunodeficiency virus type 1; knockout.

Figure 1

Siglec-1-mediated retroviral trans-infection on distinct myeloid antigen-presenting cells (APCs). Human immunodeficiency virus type 1 (HIV-1) capture via Siglec-1 and subsequent transfer to target cells has been reported not only in human APCs derived in vitro but also in activated primary myeloid cells isolated ex vivo. In murine models, Siglec-1 retroviral trans-infection has been reported ex vivo, and most importantly, due to the extraordinary ability of Siglec-1 positive APCs to capture cell-free viruses from the lymphatic vessels at the edges of the lymphoid tissue and their capacity to transfer that infectivity to permissive lymphocytes, this mechanism has also been observed in vivo.

Figure 2

Challenges to interpret human knockout genetics in infectious diseases. The study of Siglec-1 null individuals infected with human immunodeficiency virus type 1 highlights the barriers to understand the in vivo role of human knockout genes. Limitations arises from: the need to study large cohorts that can be restricted to specific populations where the variant of interest has the highest frequency; the lack of critical clinical information even in cohorts with good follow-up; the introduction of therapies that unmask any putative effect of the studied variant; and the co-infection with additional pathogens that might influence the observed phenotype in the opposite direction from what is expected.