scholarly journals Failure of dideoxynucleosides to inhibit human immunodeficiency virus replication in cultured human macrophages.

1987 ◽  
Vol 166 (4) ◽  
pp. 1144-1149 ◽  
Author(s):  
D D Richman ◽  
R S Kornbluth ◽  
D A Carson
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Monocyte ◽  
Human Immunodeficiency Virus Replication ◽  
Hiv Replication ◽  
New Therapeutic Approaches ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
T Lymphoblasts ◽  
Anti Hiv Agents

Primary human monocyte-derived macrophages (MDM) were shown to have diminished deoxynucleoside kinase activities compared to T lymphoblasts, and a reduced ability to phosphorylate dideoxynucleosides with anti-human immunodeficiency virus (HIV) activity. These drugs, azidothymidine (AZT), dideoxycytidine (ddC), and dideoxyadenosine (ddA), which are potent anti-HIV agents in CD4 lymphocytes, did not inhibit HIV replication in MDM, even at concentrations of 100 microM. This drug concentration of AZT is approximately 100-fold higher than the levels attained in the serum of treated patients and the levels required to inhibit HIV replication in lymphocytes. These observations may explain the failure of AZT therapy to clear viremia, consistent with the presence of a drug-resistant reservoir of infected cells in vivo. New therapeutic approaches to inhibit the replication of HIV in MDM may be needed.

scholarly journals A genetic-algorithm approach to simulating human immunodeficiency virus evolution reveals the strong impact of multiply infected cells and recombination

2005 ◽  
Vol 86 (11) ◽  
pp. 3109-3118 ◽  
Author(s):  
Gennady Bocharov ◽  
Neville J. Ford ◽  
John Edwards ◽  
Tanja Breinig ◽  
Simon Wain-Hobson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Copy Number ◽  
Hamming Distance ◽  
Point Mutations ◽  
Strong Impact ◽  
Hiv Replication ◽  
Immunodeficiency Virus ◽  
Genetic Algorithm Approach ◽  
Infected Cells

It has been previously shown that the majority of human immunodeficiency virus type 1 (HIV-1)-infected splenocytes can harbour multiple, divergent proviruses with a copy number ranging from one to eight. This implies that, besides point mutations, recombination should be considered as an important mechanism in the evolution of HIV within an infected host. To explore in detail the possible contributions of multi-infection and recombination to HIV evolution, the effects of major microscopic parameters of HIV replication (i.e. the point-mutation rate, the crossover number, the recombination rate and the provirus copy number) on macroscopic characteristics (such as the Hamming distance and the abundance of n-point mutants) have been simulated in silico. Simulations predict that multiple provirus copies per infected cell and recombination act in synergy to speed up the development of sequence diversity. Point mutations can be fixed for some time without fitness selection. The time needed for the selection of multiple mutations with increased fitness is highly variable, supporting the view that stochastic processes may contribute substantially to the kinetics of HIV variation in vivo.

Human herpesvirus 8 enhances human immunodeficiency virus replication in acutely infected cells and induces reactivation in latently infected cells

Blood ◽  
2005 ◽  
Vol 106 (8) ◽  
pp. 2790-2797 ◽  
Author(s):  
Elisabetta Caselli ◽  
Monica Galvan ◽  
Enzo Cassai ◽  
Arnaldo Caruso ◽  
Laura Sighinolfi ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Endothelial Cells ◽  
Mononuclear Cells ◽  
Human Herpesvirus ◽  
Human Herpesvirus 8 ◽  
Human Immunodeficiency Virus Replication ◽  
Hiv Replication ◽  
Herpesvirus 8 ◽  
Immunodeficiency Virus ◽  
Infected Cells

AbstractHuman herpesvirus 8 (HHV-8) is etiologically associated with Kaposi sarcoma (KS), the most common AIDS-associated malignancy. Previous results indicate that the HHV-8 viral transactivator ORF50 interacts synergistically with Tat protein in the transactivation of human immunodeficiency virus (HIV) long terminal repeat (LTR), leading to increased cell susceptibility to HIV infection. Here, we analyze the effect of HHV-8 infection on HIV replication in monocyte-macrophage and endothelial cells, as potential targets of coinfection. Primary or transformed monocytic and endothelial cells were infected with a cell-free HHV-8 inoculum and subsequently infected with lymphotropic or monocytotropic strains of HIV. The results show that HHV-8 coinfection markedly increases HIV replication in both cell types. HHV-8 infection induces also HIV reactivation in chronically infected cell lines and in peripheral blood mononuclear cells (PBMCs) from patients with asymptomatic HIV, suggesting the possibility that similar interactions might take place also in vivo. Furthermore, coinfection is not an essential condition, since contiguity of differently infected cells is sufficient for HIV reactivation. The results suggest that HHV-8 might be a cofactor for HIV progression and that HHV-8-infected endothelial cells might play a relevant role in transendothelial HIV spread. (Blood. 2005;106:2790-2797)

scholarly journals Vpr Is Required for Efficient Nef Expression from Unintegrated Human Immunodeficiency Virus Type 1 DNA

2007 ◽  
Vol 81 (19) ◽  
pp. 10515-10523 ◽  
Author(s):  
Betty Poon ◽  
Michael A. Chang ◽  
Irvin S. Y. Chen
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Rna ◽  
Productive Infection ◽  
Hiv Replication ◽  
Viral Dna ◽  
Hiv Tat ◽  
Immunodeficiency Virus ◽  
Unintegrated Dna ◽  
Infected Cells

ABSTRACT Unintegrated human immunodeficiency virus (HIV) DNA are viral DNA products formed naturally during HIV replication. While the integrated proviral DNA form is transcriptionally active and results in productive infection, unintegrated DNA is also capable of expression of viral RNA and proteins. Previously, we showed that HIV Vpr enhances expression from integrase-defective HIV. Here we show that Vpr activation of expression is partially dependent upon the presence of a transcriptionally active HIV promoter and results in increased transcription of unspliced gag and spliced nef viral RNA. While Tat is detectable during infection with integrase-defective HIV, Tat levels are not affected by the presence of Vpr. Mutation studies reveal that Tat is dispensable for the Vpr-mediated enhancement of expression from unintegrated DNA. We find that virion-associated Vpr is sufficient for Nef expression from unintegrated viral DNA, resulting in the efficient downregulation of CD4 from the surface of infected cells. These results provide a mechanism by which Nef expression from unintegrated HIV type 1 DNA expression occurs.

scholarly journals How Many Human Immunodeficiency Virus Type 1-Infected Target Cells Can a Cytotoxic T-Lymphocyte Kill?

2005 ◽  
Vol 79 (21) ◽  
pp. 13579-13586 ◽  
Author(s):  
W. David Wick ◽  
Otto O. Yang ◽  
Lawrence Corey ◽  
Steven G. Self
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Target Cells ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT The antiviral role of CD8+ cytotoxic T lymphocytes (CTLs) in human immunodeficiency virus type 1 (HIV-1) infection is poorly understood. Specifically, the degree to which CTLs reduce viral replication by killing HIV-1-infected cells in vivo is not known. Here we employ mathematical models of the infection process and CTL action to estimate the rate that CTLs can kill HIV-1-infected cells from in vitro and in vivo data. Our estimates, which are surprisingly consistent considering the disparities between the two experimental systems, demonstrate that on average CTLs can kill from 0.7 to 3 infected target cells per day, with the variability in this figure due to epitope specificity or other factors. These results are compatible with the observed decline in viremia after primary infection being primarily a consequence of CTL activity and have interesting implications for vaccine design.

scholarly journals Anti-Human Immunodeficiency Virus Activity of Tau Interferon in Human Macrophages: Involvement of Cellular Factors and β-Chemokines

2003 ◽  
Vol 77 (23) ◽  
pp. 12914-12920 ◽  
Author(s):  
Christine Rogez ◽  
Marc Martin ◽  
Nathalie Dereuddre-Bosquet ◽  
Jacques Martal ◽  
Dominique Dormont ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Monocyte ◽  
Type I ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
Hiv Replication ◽  
Human Macrophages ◽  
Hiv Rna ◽  
Type I Ifns ◽  
Immunodeficiency Virus

ABSTRACT Tau interferon (IFN-τ) is a noncytotoxic type I IFN responsible for maternal recognition of the fetus in ruminants. IFN-τ inhibits human immunodeficiency virus (HIV) replication more strongly than human IFN-α, particularly in human monocyte-derived macrophages. In this study performed in human macrophages, IFN-τ efficiently inhibited the early steps of the biological cycle of HIV, decreasing intracellular HIV RNA and inhibiting the initiation of the reverse transcription of viral RNA into proviral DNA. Two mechanisms induced by IFN-τ treatment in macrophages may account for this inhibition: (i) the synthesis of the cellular antiviral factors such as 2′,5′-oligoadenylate synthetase/RNase L and MxA protein and (ii) an increased production of MIP-1α, MIP-1β, and RANTES, which are natural ligands of CCR5, the principal coreceptor of HIV on macrophages. Our results suggest that IFN-τ induces the same antiviral pathways in macrophages as other type I IFNs but without associated toxicity.

scholarly journals Human cytomegalovirus modulation of CCR5 expression on myeloid cells affects susceptibility to human immunodeficiency virus type 1 infection

2006 ◽  
Vol 87 (8) ◽  
pp. 2171-2180 ◽  
Author(s):  
Christine A. King ◽  
Joan Baillie ◽  
John H. Sinclair
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Cytomegalovirus ◽  
Cell Types ◽  
Ccr5 Expression ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Bystander Cells ◽  
Hiv 1

For some time there has been evidence suggesting an interaction between human cytomegalovirus (HCMV) and Human immunodeficiency virus (HIV) in the pathogenesis of AIDS. Here, the interaction of HCMV and HIV-1 was examined in monocyte/macrophage cells, two cell types known to be targets for both viruses in vivo. Infection experiments demonstrated that prior infection with HCMV impeded subsequent superinfection with HIV-1. In contrast, uninfected bystander cells within the population were still permissive for HIV-1 infection and were also found to express increased levels of Gag after HIV-1 superinfection. Analysis of CCR5, a co-receptor for HIV-1, on HCMV-infected and bystander cells showed a substantial loss of surface CCR5 expression on infected cells due to HCMV-induced reduction of total cellular CCR5. In contrast, uninfected bystander cells displayed increased surface CCR5 expression. Furthermore, the data suggested that soluble factor(s) secreted from HCMV-infected cells were responsible for the observed upregulation of CCR5 on uninfected bystander cells. Taken together, these results suggest that, whilst HCMV-infected monocytes/macrophages are refractory to infection with HIV-1, HCMV-uninfected bystander cells within a population are more susceptible to HIV-1 infection. On this basis, HCMV infection may contribute to the pathogenesis of HIV-1.

scholarly journals Use of recombinant viruses to assess the pattern of early human immunodeficiency virus breakthrough infection in the presence of stavudine

1999 ◽  
Vol 80 (9) ◽  
pp. 2361-2367
Author(s):  
Daniel J. Medina ◽  
Peter P. Tung ◽  
Roger K. Strair
Keyword(s):  
Human Immunodeficiency Virus ◽  
High Efficiency ◽  
Mononuclear Cells ◽  
Cell Types ◽  
Small Subset ◽  
Hiv Replication ◽  
Recombinant Viruses ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Early Human

A variety of cell lines were infected with replication-defective recombinant retroviruses in the presence of stavudine (d4T). Cells which were infected despite the presence of d4T were isolated and subjected to infection with other retroviruses [replication-competent human immunodeficiency virus (HIV), replication-defective HIV or replication-defective recombinant murine retroviruses]. Each of the host cell types tested had a small subset of cells that were infected with HIV or murine retroviruses in the presence of d4T. Some of these infected cells could be infected repeatedly at high efficiency in the presence of d4T. This phenotype of ‘persistent refractoriness’ to the antiviral effects of d4T could be overcome by the addition of 5-fluoro-2-deoxyuridine (floxuridine) to d4T. The d4T–floxuridine combination also had potent antiretroviral effects in primary blood mononuclear cells.

Effects of bone marrow stimulatory cytokines on human immunodeficiency virus replication and the antiviral activity of dideoxynucleosides in cultures of monocyte/macrophages

Blood ◽  
1992 ◽  
Vol 80 (4) ◽  
pp. 995-1003 ◽  
Author(s):  
CF Perno ◽  
DA Cooney ◽  
WY Gao ◽  
Z Hao ◽  
DG Johns ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Immunodeficiency Virus ◽  
Human Peripheral Blood ◽  
Peripheral Blood Monocyte ◽  
Human Immunodeficiency Virus Replication ◽  
Hiv Replication ◽  
Gm Csf ◽  
Immunodeficiency Virus ◽  
Human Peripheral Blood Monocyte ◽  
Anti Hiv

Abstract Cells of the monocyte lineage are important targets for the replication of human immunodeficiency virus (HIV). Our group and others have previously shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates HIV replication in monocyte/macrophages, but that it also enhances the anti-HIV activity of 2′,3′-dideoxy-3′- azidothymidine (AZT). In the present study, we have explored the effects of other bone marrow stimulatory cytokines on the replication of HIV and on the anti-HIV activity of certain dideoxynucleosides in human peripheral blood monocyte/macrophages (M/M). Like GM-CSF, macrophage CSF (M-CSF) enhanced HIV replication in M/M. In contrast, granulocyte CSF (G-CSF) and erythropoietin (Epo) had no such effects. The anti-HIV activity of zidovudine (AZT) was increased in M/M exposed to GM-CSF. In contrast, the anti-HIV activity of AZT was unchanged in M/M exposed to M-CSF, and the activities of 2′,3′-dideoxycytidine (ddC) and 2′,3′-dideoxyinosine (ddl) were unchanged or slightly diminished in M/M stimulated with GM-CSF or M-CSF. These differential activities of AZT and ddC were paralleled by differential effects of the cytokines on the anabolism of these drugs to their active 5′-triphosphate moieties. GM-CSF increased the levels of AZT-5′-triphosphate (at least in part through an increase in thymidine kinase activity) and overall induced an increase in the ratio of AZT-5′-triphosphate/thymidine-5′- triphosphate. In contrast, M-CSF-induced increases in AZT-5′- triphosphate were roughly matched by increases in thymidine-5′- triphosphate. Also, GM-CSF- or M-CSF-induced increases in the levels of ddC-5′-triphosphate were associated with parallel increases in the levels of deoxycytidine-5′-triphosphate (the physiologic nucleoside that competes at the level of reverse transcriptase), so that there was relatively little net change in the ddC-5′-triphosphate/deoxycytidine- 5′-triphosphate ratio. Thus, bone marrow stimulatory cytokines may have a variety of effects on HIV replication and on the activity and metabolism of dideoxynucleosides in M/M.

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