Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topotecan (TPT), a known inhibitor of topoisomerase I, has previously been shown to inhibit the replication of several viruses. The mechanism of inhibition was proposed to be the inhibition of topoisomerase I. We report that TPT decreased replication of human immunodeficiency virus type 1 (HIV-1) in CPT-K5, a cell line with a topoisomerase I mutation. TPT inhibited production of HIV-1 RNA and p24 in CPT-K5 and wild-type cells equally effectively. The antiviral effects of TPT were observed not only in the topoisomerase-mutated CPT-K5 line but also in peripheral blood mononuclear cells (PBMC) acutely infected with clinical isolates and in OM10.1 cells latently infected with HIV and activated by tumor necrosis factor alpha. Little toxicity from TPT was noted in HIV-1-infected PBMC and in CPT-K5 and OM10.1 cells as measured by cell growth and proliferation assays. These observations suggest that TPT targets factors in virus replication other than cellular topoisomerase I and inhibits cytokine-mediated activation in latently infected cells by means other than cytotoxicity. These results suggest a potential for TPT and for other camptothecins in anti-HIV therapy alone and in combination with other antiretroviral drugs.
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PMID:Topotecan inhibits human immunodeficiency virus type 1 infection through a topoisomerase-independent mechanism in a cell line with altered topoisomerase I. 914 55

CCR5 ligands RANTES, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta are potent and specific inhibitors of strains of human immunodeficiency virus (HIV) that use CCR5 as a receptor, which are the strains most involved in primary infection. Recently, we observed that release of CCR5 ligands is a consistent and reproducible parameter of response to antigen activation in studies using PBMC. In this study, we show that CCR5 ligands are released upon antigen [Fragment C of tetanus toxin (TTC)] stimulation in 81% (n = 16) of subjects tested, as detected by a standard ELISA in tissue culture supernatants of antigen-activated cells. In contrast, ELISA for other cytokines from the same supernatants revealed that IFN-gamma release could be detected only in 31% of subjects, IL-2 could be detected only in 12% of the subjects and IL-4 was not detectable in any of the subjects tested. Similarly, proliferative responses to TTC, as measured by a standard tritiated thymidine incorporation assay, were detectable in only 56% of the subjects. Similar observations have been reported in flow cytometric studies, and resonate with previous findings emphasizing the role of CCR5 in T cell responses. In addition, the levels of CCR5 ligands in supernatants from antigen-activated cells were sufficient to inhibit infection of R5 HIV. Thus, CCR5 ligands might play a role in controlling HIV in vivo. Taken together, these observations suggest that CCR5 ligands, and in particular MIP-1alpha and MIP-1beta, released in the course of memory responses may play a role in protecting CD4(+) memory T cells from infection.
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PMID:Recall antigen activation induces prompt release of CCR5 ligands from PBMC: implication in memory responses and immunization. 1546 54