The Role of Mononuclear Phagocytes in HTLV-III/LAV Infection

Gartner, Suzanne; Markovits, P; Markovitz, David M.; Kaplan, Mark H.; Gallo, Robert C.; Popovič, Mikuláš

doi:10.1126/science.3014648

Cited by 1,739 publications

(857 citation statements)

References 35 publications

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“…This finding is consistent with the knowledge that macrophages are a long-lived HIV reservoir, thereby providing a continuous source of virus for de novo infection of susceptible target cells that reside and/or circulate in the lymphoid tissue (35)(36)(37).…”

Section: Discussionsupporting

confidence: 91%

HIV-Associated Multinucleated Giant Cells in Lymphoid Tissue of the Waldeyer's Ring: A Detailed Study

et al. 2000

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Hyperplastic lymphoid tissues of the Waldeyer's ring in human immunodeficiency virus (HIV)-infected patients may occasionally contain multinucleated giant cells (MGCs). These cells, which are unrelated to any opportunistic infection, previously have been demonstrated to harbor significant amounts of HIV. Studies undertaken to characterize these MGCs have generated conflicting results: some reports suggested a macrophage origin, whereas others supported a dendritic cell lineage. This study was performed to determine the occurrence of MGCs in a series of adenoid/tonsil specimens from HIV-seropositive patients showing no histological evidence of opportunistic infection in order to further characterize the phenotype of these cells and to investigate the role of a viral infection in their pathogenesis. Adenoid/tonsil tissue specimens from 21 HIV-seropositive patients with no documented opportunistic infection were scrutinized for the presence of MGCs and evaluated immunohistochemically on paraffin sections by antibodies directed against various macrophage and DC antigens. These antigens included CD68, the macrophage marker 3A5, major histocompatibility complex Class II, S-100 protein, CD1a, and CD83. Additional immunostainings directed at CD21 and CD35 as well as at the HIV-associated p24 antigen were also performed. Finally, the presence of Epstein-Barr virus and human herpesvirus 8 viral sequences was investigated by in situ hybridization and by polymerase chain reaction analysis, respectively. MGCs were found in 14 patients (66.7%), regardless of gender, age, method of viral transmission, CD4 cell count, viral load, or ethnic group. These cells were mostly localized at the lymphoepithelium layer of the tonsillar crypts and, to a lesser extent, in the interfollicular areas of the underlying lymphoid tissue, which consistently exhibited features of follicular hyperplasia. Phenotypically, MGCs were found to be CD68 ؉ , 3A5 ؉ , major histocompatibility complex Class II ؉ , S-100 protein ؉/؊ , CD1a ؊ , CD21 ؊ , CD35 ؊ , and CD83 ؊ . Although the HIV-associated p24 protein was consistently present in the cytoplasm of these cells, no sign of Epstein-Barr virus or human herpesvirus 8 infection could be demonstrated. Consequently, our study didn't show any conclusive evidence to support that MGCs in hyperplastic lymphoid tissues of the Waldeyer's ring from HIV-seropositive patients originated from dendritic cells. The definite nature of these cells has yet to be elucidated, but it is plausible that they simply represent activated macrophages that are infected with HIV present in the oropharyngeal secretions during the circulation of their precursor through the lymphoepithelium area of adenoids and tonsils.

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Section: Discussionsupporting

confidence: 91%

HIV-Associated Multinucleated Giant Cells in Lymphoid Tissue of the Waldeyer's Ring: A Detailed Study

et al. 2000

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“…Recently, we and others reported that the low dNTP pool in macrophages is partially due to active hydrolysis of cellular dNTPs by SAMHD1, a cellular dNTP triphosphohydrolase (5,6). Although the dNTP pools differ considerably, both cell types have similarly high concentrations of ribonucleoside triphosphates (rNTPs) 2 (4). In addition, it has been shown that this disparity exists in yeast (7).…”

mentioning

confidence: 99%

“…Human immunodeficiency virus type 1 (HIV-1) uniquely infects both activated CD4 ϩ T cells and terminally differentiated/ non-dividing macrophages (1,2). These cells differ in the concentrations of their intracellular deoxyribonucleoside triphosphates (dNTPs).…”

mentioning

confidence: 99%

Effect of Ribonucleotides Embedded in a DNA Template on HIV-1 Reverse Transcription Kinetics and Fidelity

Daddacha

Noble²,

Nguyen

et al. 2013

Journal of Biological Chemistry

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Background: Under limiting dNTP concentrations, HIV-1 RT incorporates rNTPs during DNA synthesis. Results: HIV-1 RT utilizes dNTP less efficiently around rNMPs, and mismatch extension fidelity is significantly reduced. Conclusion: Presence of an rNMP in DNA template slows HIV-1 RT-mediated DNA synthesis and reduces fidelity. Significance: This study provides insight into how rNMP incorporation during proviral DNA synthesis can affect HIV-1 replication kinetics and fidelity.

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“…The presence of an extravascular reservoir of human immunodeficiency virus type 1 (HIV-1)-infected macrophages is well established (6,7,10,12,30,31). The ability of tissue macrophages to serve as a reservoir for HIV-1 and simian immunodeficiency virus replication correlates with the ability of monocyte-derived macrophages to support productive viral infection in vitro (reviewed in reference 10).…”

mentioning

confidence: 99%

Characterization of Restrictions to Human Immunodeficiency Virus Type 1 Infection of Monocytes

Triques

Stevenson

2004

J Virol

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Tissue macrophages are an important cellular reservoir for replication of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus. In vitro, the ability of macrophages to support viral replication is differentiation dependent in that precursor monocytes are refractory to infection. There is, however, no consensus as to the exact point at which infection is restricted in monocytes. We have revisited this issue and have compared the efficiencies of early HIV-1 replication events in monocytes and in differentiated macrophages. Although virus entry in monocytes was comparable to that in differentiated macrophages, synthesis of full-length viral cDNAs was very inefficient. Relative to differentiated macrophages, monocytes contained low levels of dTTP due to low thymidine phosphorylase activity. Exogenous addition of D-thymidine increased dTTP levels to that in differentiated macrophages but did not correct the reverse transcription defect. These results point to a restriction in monocytes that is independent of reverse transcription precursors and suggest that differentiation-dependent cellular cofactors of reverse transcription are rate limiting in monocytes.

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The Role of Mononuclear Phagocytes in HTLV-III/LAV Infection

Cited by 1,739 publications

References 35 publications

HIV-Associated Multinucleated Giant Cells in Lymphoid Tissue of the Waldeyer's Ring: A Detailed Study

HIV-Associated Multinucleated Giant Cells in Lymphoid Tissue of the Waldeyer's Ring: A Detailed Study

Effect of Ribonucleotides Embedded in a DNA Template on HIV-1 Reverse Transcription Kinetics and Fidelity

Characterization of Restrictions to Human Immunodeficiency Virus Type 1 Infection of Monocytes

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