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

Abstract

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.

HIV-1 Nef Triggers Macrophage Fusion in a p61Hck- and Protease-Dependent Manner

“…When human macrophages infected with Dnef-HIV-1 or wt viruses were compared, we observed that formation of MGCs (or syncytia) was diminished in Dnef-HIV-1-infected cells, whereas Dnef-HIV-1 and wt-HIV-1 infectivities of human macrophages were similar. In AIDS patients, MGCs have been shown to be of macrophage origin (7)(8)(9), but the mechanisms involved in their formation in vivo or in vitro have not been studied. Also HIV-1-infected CD4 + lymphocytes form giant cells in vitro, but until now, they have not been observed in AIDS patients.…”

“…Several pathologies involve the formation of giant macrophages, but it is not clear whether it is beneficial or detrimental for patients (12). Giant macrophages have been described in the brains of AIDS patients as a marker for disease progression associated with HIV-induced dementia (7) and in lymphoid tissues of Waldeyer's ring in 66.7% of HIV-infected patients (8). HIV-infected T cells also form giant cells, but they rapidly undergo apoptosis (10), probably explaining why giant HIV-1-infected lymphocytes have not been observed in vivo.…”

“…Because macrophages have the ability to migrate through anatomic barriers, they are also involved in HIV-1 dissemination. In addition, multinucleated giant cells (MGCs) formed by HIV-1-infected macrophages have been identified in several tissues of AIDS patients, such as in lymphoid organs, colon, and brain (6)(7)(8)(9). In brain, the presence of giant macrophages has been associated with HIV-induced dementia (10) and is considered as a hallmark of AIDS progression (11,12).…”

Otorhinolaryngological findings and hearing in HIV-positive and HIV-negative children in a developing country

“…In addition, HIV involvement of the intraparotid and pharyngeal lymphoid tissue may lead to marked hypertrophy of these structures [5][6][7], whereas in the orofacial region, widespread lesions of viral and fungal infections, as well as dental caries, may occur [1,3,8]. HIV-infected children may also suffer from hearing loss of either peripheral or central origin [9,10].…”

Respiratory obstruction secondary to adenotonsillar hypertrophy in HIV disease

“…Multinucleated giant cells were present in 67% of biopsy samples of HIV patients with lymphoid hyperplasia. Their presence should suggest the possibility of an underlying HIV infection [5] . Treatment options in symptomatic patients with adenotonsillar hypertrophy have previously been limited to surgical resection.…”