Characterization of the Early Steps of Infection of Primary Blood Monocytes by Human Immunodeficiency Virus Type 1

Abstract

Blood-circulating monocytes migrate in tissues in response to danger stimuli and differentiate there into two major actors of the immune system: macrophages and dendritic cells. Given their migratory behavior and their pivotal role in the orchestration of immune responses, it is not surprising that cells of the monocyte lineage are the target of several viruses, including human immunodeficiency virus type 1 (HIV-1). HIV-1 replicates in monocytoid cells to an extent that is influenced by their differentiation status and modulated by exogenous stimulations. Unstimulated monocytes display a relative resistance to HIV infection mostly exerted during the early steps of the viral life cycle. Despite intensive studies, the identity of the affected step remains controversial, although it is generally assumed to take place after viral entry. We reexamine here the early steps of viral infection of unstimulated monocytes using vesicular stomatitis virus G protein-pseudotyped HIV-1 virions. Our data indicate that a first block to the early steps of infection of monocytes with these particles occurs at the level of viral entry. After entry, reverse transcription and integration proceed with extremely slow kinetics rather than being blocked. Once completed, viral DNA molecules delay entry into the nucleus and integration for up to 5 to 6 days. The inefficacy of these steps accounts for the resistance of monocytes to HIV-1 during the early steps of infection.

Cell adhesion through αV-containing integrins is required for efficient HIV-1 infection in macrophages

“…14,15 Unlike monocyte-derived macrophages (MDMs), undifferentiated monocytes are not readily infected by HIV-1 in cell culture. 16,17 A productive viral infection may only occur after monocytes are differentiated after serum or cytokine stimulation, 18 a process that leads to the up-regulation of different cell-surface markers and receptors, including ␣V integrins 19,20 and, more specifically, an increase in the vitronectin ␣V␤3 receptor during the first 3 to 6 hours after infection. 14 We and others have shown the antiviral effect of specific anti-␣V antibodies in MDMs.…”

Circulating Monocytes Are Not a Major Reservoir of HIV-1 in Elite Suppressors

“…These reservoirs can lead to a rebound in viremia if HAART is stopped (12), and in the case of HIV-1-infected macrophages may contribute to tissue inflammation and damage despite ongoing suppressive HAART (15,48,56). Circulating monocytes in the peripheral blood are relatively resistant to productive HIV-1 infection ex vivo prior to differentiation into tissue macrophages (38,39,52,57), which are more permissive to HIV-1 infection and viral replication (2,37,58). Despite this finding, HIV-1-infected monocytes have been identified in the peripheral blood of viremic and HAART-treated patients (3, 9, 14, 19, 26-28, 31, 33, 34, 36, 43, 49, 51, 53, 54, 62) and are thought to contribute to viral persistence (13,32).…”

Monocytes and their Role in Human Immunodeficiency Virus Pathogenesis

“…Synthesis of viral DNA molecules is completed very slowly in monocytes, as reverse transcription take place over days after infection. The majority of functional viral genomes are completed by day 4-5 post infection and then 5-6 additional days to integrate (Arfi et al, 2008). This delay in integration of viral DNA into host chromosomal DNA can be due to trafficking, nuclear import, or even postnuclear-import defects specifically present in monocytes.…”

“…Therefore, the control of viral infection in monocytes is thought to take place during the early phases of infection, after viral entry. Arfi et al (2008) showed that monocytes are susceptible to HIV-1, but the cells display several defects during HIV-1 infection, such as a slow reverse transcription and delayed nuclear import and integration (Arfi et al, 2008). Synthesis of viral DNA molecules is completed very slowly in monocytes, as reverse transcription take place over days after infection.…”