Abstract
BackgroundOral keratinocytes on the mucosal surface are frequently exposed to HIV-1 through contact with infected sexual partners or nursing mothers. To determine the plausibility that oral keratinocytes are primary targets of HIV-1, we tested the hypothesis that HIV-1 infects oral keratinocytes in a restricted manner.ResultsTo study the fate of HIV-1, immortalized oral keratinocytes (OKF6/TERT-2; TERT-2 cells) were characterized for the fate of HIV-specific RNA and DNA. At 6 h post inoculation with X4 or R5-tropic HIV-1, HIV-1gag RNA was detected maximally within TERT-2 cells. Reverse transcriptase activity in TERT-2 cells was confirmed by VSV-G-mediated infection with HIV-NL4-3Δenv-EGFP. AZT inhibited EGFP expression in a dose-dependent manner, suggesting that viral replication can be supported if receptors are bypassed. Within 3 h post inoculation, integrated HIV-1 DNA was detected in TERT-2 cell nuclei and persisted after subculture. Multiply spliced and unspliced HIV-1 mRNAs were not detectable up to 72 h post inoculation, suggesting that HIV replication may abort and that infection is non-productive. Within 48 h post inoculation, however, virus harbored by CD4 negative TERT-2 cells trans infected co-cultured peripheral blood mononuclear cells (PBMCs) or MOLT4 cells (CD4+ CCR5+) by direct cell-to-cell transfer or by releasing low levels of infectious virions. Primary tonsil epithelial cells also trans infected HIV-1 to permissive cells in a donor-specific manner.ConclusionOral keratinocytes appear, therefore, to support stable non-replicative integration, while harboring and transmitting infectious X4- or R5-tropic HIV-1 to permissive cells for up to 48 h.
Highlights
During oral-sexual contacts and breast feeding, oral keratinocytes of the stratified squamous epithelium represent the most abundant cell type exposed to infectious HIV-1 [1,2,3,4,5]
Oral keratinocytes capture and transfer HIV-1 to infect peripheral blood mononuclear cells Primary tonsil epithelial (TE) cells from six donors were compared for the ability to transfer HIV-1 to peripheral blood mononuclear cells (PBMCs) in vitro (Fig. 1A)
To avoid the subject-to-subject variability seen in primary TE cell cultures, we evaluated TERT-2 cells for further study of capture, infection, replication and transfer of HIV-1 to permissive cells
Summary
During oral-sexual contacts and breast feeding, oral keratinocytes of the stratified squamous epithelium represent the most abundant cell type exposed to infectious HIV-1 [1,2,3,4,5]. HIV-1 that is harbored in keratinocytes could be transferred to proximal immature dendritic (Langerhans) cells of the mucosal epithelium. These Langerhans cells present HIV-1 to permissive CD4+ T lymphocytes. In infant [8,9] and adult primates [10], cell-free simian immunodeficiency virus (SIV) infects intact oral mucosa within one day after non-traumatic exposure and viral RNA is detected in the proximal epithelium. The pathogenesis of SIV-infection in primates is consistent with the possibility that clinical exposures of HIV-1 to the oral and oropharyngeal mucosa result in primary infections of the keratinocytes in the squamous epithelium. To determine the plausibility that oral keratinocytes are primary targets of HIV-1, we tested the hypothesis that HIV-1 infects oral keratinocytes in a restricted manner
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