PubMed · 11366937
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P Simmons. 1999. Pathogenesis puzzle.. https://pubmed.ncbi.nlm.nih.gov/11366937/
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Recent advances in class II tetramer staining technology have allowed reliable direct ex vivo visualization of antigen-specific CD4 T cells. In order to define the frequency and phenotype of a prototype response to a nonpersistent pathogen, we have used such techniques to analyze influenza virus-specific memory CD4 T cells directly from blood. These responses are stably detectable ex vivo at low frequencies (range, 0.00012 to 0.0061% of CD4 T cells) and display a distinct "central memory" CD62L(+) phenotype.
This report describes induction of HIV-1 resistance and synthesis of resistance factors in immortal CD4-positive T lymphocytes. SupT1 cells were infected by NL4-3 attenuated by a defect in the vif gene through coculture with infected primary lymphocytes. Cell lines from this infection, termed R1, expressed CD4 and CXCR4, carried low levels of HIV-1 DNA, but expressed no other detectable viral products and were resistant to infection by wild-type HIV-1. Investigation of challenge infection in resistant R1 lines demonstrated entry, reverse transcription, and integration by incoming HIV-1 but no synthesis of viral RNA. By assay of marker gene expression, we found that Tat was unable to activate LTR-driven transcription in R1 lines. HIV-1-resistant R1 lines secreted soluble factors that inhibited productive infection of primary lymphocytes by several strains of HIV-1 and blocked viral RNA synthesis in newly infected cells. Resistance factors also blocked the induction of HIV-1 transcription in ACH-2 cells as assayed by viral antigen expression and Northern blot of viral RNA. Soluble factors produced by HIV-1-resistant, immortal R1 cells may form the basis of new approaches to control HIV-1 infection.
Rz1-9 is a multimeric hammerhead ribozyme targeted against nine highly conserved sites within the env coding region of human immunodeficiency virus type-1 (HIV-1) RNA. This ribozyme was shown to inhibit HIV-1 replication (1, 2). However, Rz1-9 target sites are only conserved within the clade B of HIV-1. In this study, we have designed another multimeric ribozyme, Rz10-14. This multimeric ribozyme is targeted against five sites that are highly conserved amongst all major clades of HIV-1. A third multimeric ribozyme, Rz1-14, was obtained by combining both Rz1-9 and Rz10-14. A mouse stem cell virus-based MGIN vector (3) was used to express these ribozymes in a human CD4+ T lymphoid cell line. Stable transductants expressed vector RNA containing ribozymes which were shown to be active. In HIV-1 challenge experiments, very little or no virus production could be detected in the pools of stable MT4 transductants expressing Rz1-14 for 60 days tested. Inhibition of virus replication was most prominent with Rz1-14, followed by Rz1-9, and then Rz10-14. Thus, the combined multimeric ribozyme, Rz1-14, is more effective than Rz1-9 or Rz10-14. As Rz1-14 is targeted against all major clades of HIV-1, it will be further pursued for use in HIV-1 gene therapy.