Immature Dendritic Cells Selectively Replicate Macrophagetropic (M-Tropic) Human Immunodeficiency Virus Type 1, while Mature Cells Efficiently Transmit both M- and T-Tropic Virus to T Cells

Abstract

Dendritic cells (DCs) can develop from CD14+ peripheral blood monocytes cultured in granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4). By 6 days in culture, the cells have the characteristics of immature DCs and can be further induced to mature by inflammatory stimuli or by monocyte-conditioned medium. After infection with macrophagetropic (M-tropic) human immunodeficiency virus type 1 (HIV-1), monocytes and mature DCs show a block in reverse transcription and only form early transcripts that can be amplified with primers for the R/U5 region. In contrast, immature DCs cultured for 6 or 11 days in GM-CSF and IL-4 complete reverse transcription and show a strong signal when LTR/gag primers are used. Blood monocytes and mature DCs do not replicate HIV-1, whereas immature DCs can be productively infected, but only with M-tropic HIV-1. The virus produced by immature DCs readily infects activated T cells. Although mature DCs do not produce virus, these cells transmit both M- and T-tropic virus to T cells. In the cocultures, both DCs and T cells must express functional chemokine coreceptors for viral replication to occur. Therefore, the developmental stage of DCs can influence the interaction of these cells with HIV-1 and influence the extent to which M-tropic and T-tropic virus can replicate.

Vaccine-induced enhancement of viral infections

“…Recent studies suggest that feline dendritic cells (feDC) play a role in the transmission of FIV comparable to that of human DC and HIV infection. It was shown in vitro that feDC can increase FIV infection of resting cells, but in particular of activated CD4 + Tcells [114,115], which is reminiscent of in vivo results obtained for HIV and SIV [89,116,117]. Early studies showed that FIV can interact with C-type lectin receptors, like human DC-SIGN, and that this interaction facilitated FIV infection in trans [118], similar to the mechanism described for HIV-1 (see above).…”

“…More interestingly, infection may also occur in trans, when the DC delivers the infectious particle to T-cells that interact with the DC [84,86]. In this regard, mature DC has been shown to increase transmission of both R5 and X4 viruses to T-cells [87][88][89][90]. The precise involvement of DC-SIGN in this process is still unclear [91].…”

The interaction of HIV with dendritic cells: outcomes and pathways

“…In vitro, different sources of DCs and LCs have been used to detect infection with HIV. These include LCs from skin [17][18][19][20] and vagina [21], different subsets of DCs in blood [22][23][24], and DCs generated in large numbers from monocytes [25][26][27][28] or from CD34 + progenitors [29]. In each case it is possible to demonstrate infection of some DCs, but again the frequency is low, particularly relative to cultures of CD4 + T cells.…”

“…Only several percent or less of the DCs in the cultures express detectable levels of newly synthesized viral protein (e.g. HIV gag p24), and immature forms of DCs are more susceptible to productive infection [25].…”

“…Recent in vitro studies addressed some of the potential explanations for the relatively inefficient productive infection of HIV of DCs and LCs. Several reports have demonstrated that HIV using CCR5 [chemokine (C-C motif) receptor 5], R5 HIV, replicates better than HIV using CXCR4 [chemokine (C-X-C motif) receptor 4], X4 HIV, in DCs and LCs ex vivo [19,25,30,31]. The immature DCs and LCs might not express CXCR4, [32] which could provide a simple explanation for the restriction of X4 HIV replication in DCs or LCs.…”