Cellular tropism of the human retrovirus HTLV-III/LAV. I. Role of T cell activation and expression of the T4 antigen.

Abstract

In cultures of normal human lymphocytes infected with the human retrovirus HTLV-III/LAV, detectable cytoplasmic virus appears and then disappears in a proportion (1 to 10%) of cells, followed by release of virus detected by particulate reverse transcriptase activity, virus antigen assay, and infectivity titer. Virus infection is associated with loss of detectable T4 antigen on infected cells and, ultimately, complete loss of T4+ cells from the culture. Residual non-T4+ cells are not susceptible to a second infection with HTLV-III/LAV, and in cultures of separated cell populations, substantial virus replication occurred in T4+ T cells and minimally, if at all, in non-T4+ cells. We could not detect a disproportionate loss of cell surface phenotype (other than T4) in comparison of infected and noninfected cultures of lymphocytes or purified T4+ T cells when these cultures were monitored with a panel of monoclonal antibodies that detect the major mononuclear cell types (alpha-T11, alpha-T3, alpha-Mo2, alpha-B1), functional T cell subsets (alpha-T8, alpha-Leu-8, alpha-T17), or activated/proliferating cells (alpha-T10, alpha-Ia, alpha-T9, alpha-4F2, alpha-Tac). HTLV-III/LAV replication was quantitatively greatest in lymphocytes stimulated with phytohemagglutinin (PHA) and cultured in the presence of interleukin 2 (IL 2). Once activated by PHA, virus production in nondividing (irradiated) cells was similar to that in nonirradiated cells, but was substantially reduced if radiation was performed before PHA stimulation. Omission of PHA, IL 2, or both resulted in progressively lower amounts of virus replication. However, virus replication was detected and T4+ T cell depletion occurred in all cultures, regardless of medium supplement or radiation. T4+ T cells absorb infectious virus, and the binding of HTLV-III/LAV to the surface of T4+ T cells, but not to non-T4+ cells, was directly demonstrated. Binding is equivalent in activated and nonactivated cells and at 4 degrees and 37 degrees C. Reciprocal inhibition of binding was observed with alpha-T4a monoclonal antibody and virus. Exposure of cells to alpha-T4a before and during HTLV-III/LAV inoculation inhibited subsequent virus replication. We conclude that T4+ T cells are the major target for HTLV-III/LAV replication, that this tropism is related to expression of the T4 antigen that serves as a binding site for virus, that infection is inexorable in T4+ T cells regardless of subset or activation state, and that the activation/proliferative state of the cells is not a necessary determinant of infectivity, but rather, determines the amount of replication that will ensue.

IL-31 expression in HIV-infected patients with different routes of disease transmission

“…The findings of the present study may, therefore, suggest that IL-31 plays a significant role in sexual transmission of HIV, rather than in the blood transmission of HIV, mainly via skin and mucous membranes. This inference is supported by the findings of most of the recent studies, which have reported the association of IL-31 levels with allergic diseases, spontaneous asthma, inflammatory bowel disease, and chronic urticarial [25,26,34] …”

“…The present study also revealed significantly higher levels of IL-31 in patients infected through the sexual transmission of HIV compared to those infected through blood transmission ( P < .01). This could be because the mucosal immune system is the storehouse of activated CD4 + cells, [25] where HIV replicates further efficiently [26,27] . The CD4 + cells harbor IL-31, leading to increased cytokine concentrations in these cells.…”

“…This inference is supported by the findings of most of the recent studies, which have reported the association of IL-31 levels with allergic diseases, spontaneous asthma, inflammatory bowel disease, and chronic urticarial. [25,26,34] CD4 + cells serve as important indicators of disease progression and treatment response in HIV-infected patients. These cells are also the most important cell type for IL-31 production.…”

“…This could be because the mucosal immune system is the storehouse of activated CD4 + cells, [25] where HIV replicates further efficiently. [26,27] The CD4 + cells harbor IL-31, leading to increased cytokine concentrations in these cells. This could account for the increased levels of IL-31 in patients infected through sexual transmission compared to those infected due to blood transmission of HIV.…”