Synergistic Inhibition of Primary Isolates of Human Immunodeficiency Virus Type 1 by Combinations of 3′-Fluoro-3′-Deoxythymidine and 2′,3′-Dideoxyinosine

1993 ◽  
Vol 4 (4) ◽  
pp. 241-244 ◽  
Author(s):  
S. W. Cox ◽  
J. Albert ◽  
K. Aperia ◽  
B. Wahren
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Antiviral Effect ◽  
Clinical Situation ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
The Individual

We examined the antiviral effect against human immunodeficiency virus type 1 of 3′-fluoro-3′-deoxythymidine and 2′,3′-dideoxyinosine, both alone and in combination. Primary isolates of human immunodeficiency virus were used directly after isolation on peripheral blood mononuclear cells, without culturing on established cell lines, in order to maintain close similarity to the clinical situation. All isolates were synergistically inhibited by combinations of the drugs, though their susceptibility to the separate drugs varied. The selectivity indices of the combinations were similar to that of the individual drugs. The synergistic combination of 3′-fluoro-3′-deoxythymidine and 2′,3′-dideoxyinosine appears promising for the treatment of human immunodeficiency virus infection and deserves further investigation.

scholarly journals Design and Profiling of GS-9148, a Novel Nucleotide Analog Active against Nucleoside-Resistant Variants of Human Immunodeficiency Virus Type 1, and Its Orally Bioavailable Phosphonoamidate Prodrug, GS-9131

2007 ◽  
Vol 52 (2) ◽  
pp. 655-665 ◽  
Author(s):  
Tomas Cihlar ◽  
Adrian S. Ray ◽  
Constantine G. Boojamra ◽  
Lijun Zhang ◽  
Hon Hui ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Biological Properties ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] is a novel ribose-modified human immunodeficiency virus type 1 (HIV-1) nucleotide reverse transcriptase (RT) inhibitor (NRTI) selected from a series of nucleoside phosphonate analogs for its favorable in vitro biological properties including (i) a low potential for mitochondrial toxicity, (ii) a minimal cytotoxicity in renal proximal tubule cells and other cell types, (iii) synergy in combination with other antiretrovirals, and (iv) a unique resistance profile against multiple NRTI-resistant HIV-1 strains. Notably, antiviral resistance analysis indicated that neither the K65R, L74V, or M184V RT mutation nor their combinations had any effect on the antiretroviral activity of GS-9148. Viruses carrying four or more thymidine analog mutations showed a substantially smaller change in GS-9148 activity relative to that observed with most marketed NRTIs. GS-9131, an ethylalaninyl phosphonoamidate prodrug designed to maximize the intracellular delivery of GS-9148, is a potent inhibitor of multiple subtypes of HIV-1 clinical isolates, with a mean 50% effective concentration of 37 nM. Inside cells, GS-9131 is readily hydrolyzed to GS-9148, which is further phosphorylated to its active diphosphate metabolite (A. S. Ray, J. E. Vela, C. G. Boojamra, L. Zhang, H. Hui, C. Callebaut, K. Stray, K.-Y. Lin, Y. Gao, R. L. Mackman, and T. Cihlar, Antimicrob. Agents Chemother. 52:648-654, 2008). GS-9148 diphosphate acts as a competitive inhibitor of RT with respect to dATP (Ki = 0.8 μM) and exhibits low inhibitory potency against host polymerases including DNA polymerase γ. Oral administration of GS-9131 to beagle dogs at a dose of 3 mg/kg of body weight resulted in high and persistent levels of GS-9148 diphosphate in peripheral blood mononuclear cells (with a maximum intracellular concentration of >9 μM and a half-life of >24 h). This favorable preclinical profile makes GS-9131 an attractive clinical development candidate for the treatment of patients infected with NRTI-resistant HIV.

scholarly journals Inhibition of Human Immunodeficiency Virus Type 1 Replication by Combination of Transcription Inhibitor K-12 and Other Antiretroviral Agents in Acutely and Chronically Infected Cells

1999 ◽  
Vol 43 (3) ◽  
pp. 492-497 ◽  
Author(s):  
Mika Okamoto ◽  
Takashi Okamoto ◽  
Masanori Baba
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Antiretroviral Agents ◽  
Immunodeficiency Virus ◽  
K 12 ◽  
Hiv 1

ABSTRACT 8 - Difluoromethoxy - 1 - ethyl - 6 - fluoro - 1,4 - dihydro - 7 - [4 - (2 - methoxyphenyl) - 1 - piperazinyl] - 4 - oxoquinoline - 3 - carboxylic acid (K-12) has recently been identified as a potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) transcription. In this study, we examined several combinations of K-12 and other antiretroviral agents for their inhibitory effects on HIV-1 replication in acutely and chronically infected cell cultures. Combinations of K-12 and a reverse transcriptase (RT) inhibitor, either zidovudine, lamivudine, or nevirapine, synergistically inhibited HIV-1 replication in acutely infected MT-4 cells. The combination of K-12 and the protease inhibitor nelfinavir (NFV) also synergistically inhibited HIV-1, whereas the synergism of this combination was weaker than that of the combinations with the RT inhibitors. K-12 did not enhance the cytotoxicities of RT and protease inhibitors. Synergism of the combinations was also observed in acutely infected peripheral blood mononuclear cells. The combination of K-12 and cepharanthine, a nuclear factor κB inhibitor, synergistically inhibited HIV-1 production in tumor necrosis factor alpha-stimulated U1 cells, a promonocytic cell line chronically infected with the virus. In contrast, additive inhibition was observed for the combination of K-12 and NFV. These results indicate that the combinations of K-12 and clinically available antiretroviral agents may have potential as chemotherapeutic modalities for the treatment of HIV-1 infection.

Virus Burden in Human Immunodeficiency Virus Type 1-Infected Children: Relationship to Disease Status and Effect of Antiviral Therapy

PEDIATRICS ◽  
1991 ◽  
Vol 87 (6) ◽  
pp. 921-925
Author(s):  
Isaac Srugo ◽  
Philip A. Brunell ◽  
Nickolas V. Chelyapov ◽  
Victor lsraele ◽  
David D. Ho ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Tissue Culture ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Asymptomatic Children ◽  
Immunodeficiency Virus ◽  
Hiv 1

The human immunodeficiency virus type 1 (HIV-1) was isolated from the plasma and peripheral blood mononuclear cells (PBMCs) from each of 21 infected children. The mean titers in plasma were 7 and 165 tissue culture-infective doses per milliliter in 9 children with asymptomatic (P-1) and 12 with symptomatic (P-2) infection, respectively (P = .0013). Significantly higher viral titers were found in PBMCs obtained from P-2 compared with P-1 children: 1920 vs 25 tissue culture-infective doses per 106 PBMC (P = .0018). In symptomatic patients at least 1 in 520 circulating mononuclear cells harbored HIV-1. No correlation was found between the viral burden and CD4+ lymphocyte counts. A decrease in the HIV-1 titers was noted both in PBMCs and plasma of symptomatic patients treated with zidovudine for 2 to 7 months. It is concluded that symptomatic children harbor a higher amount of the virus in plasma and PBMCs than asymptomatic children. Zidovudine treatment for 2 months or more decreased the amount of HIV-1 in PBMCs and plasma.

scholarly journals Genetic and Functional Analysis of R5X4 Human Immunodeficiency Virus Type 1 Envelope Glycoproteins Derived from Two Individuals Homozygous for the CCR5Δ32 Allele

2006 ◽  
Vol 80 (7) ◽  
pp. 3684-3691 ◽  
Author(s):  
Lachlan Gray ◽  
Melissa J. Churchill ◽  
Niamh Keane ◽  
Jasminka Sterjovski ◽  
Anne M. Ellett ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Envelope Glycoproteins ◽  
Peripheral Blood Mononuclear ◽  
Transfected Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We characterized human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) isolated from two HIV-1-infected CCR5Δ32 homozygotes. Envs from both subjects used CCR5 and CXCR4 for entry into transfected cells. Most R5X4 Envs were lymphocyte-tropic and used CXCR4 exclusively for entry into peripheral blood mononuclear cells (PBMC), but a subset was dually lymphocyte- and macrophage-tropic and used either CCR5 or CXCR4 for entry into PBMC and monocyte-derived macrophages. The persistence of CCR5-using HIV-1 in two CCR5Δ32 homozygotes suggests the conserved CCR5 binding domain of Env is highly stable and provides new mechanistic insights important for HIV-1 transmission and persistence.

scholarly journals Naphthalene sulfonate polymers with CD4-blocking and anti-human immunodeficiency virus type 1 activities.

1996 ◽  
Vol 40 (1) ◽  
pp. 234-236 ◽  
Author(s):  
S Rusconi ◽  
M Moonis ◽  
D P Merrill ◽  
P V Pallai ◽  
E A Neidhardt ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
T Cell Proliferation ◽  
Peripheral Blood Mononuclear ◽  
Primary Monocyte ◽  
Immunodeficiency Virus ◽  
Blood Mononuclear Cells

PIC 024-4 and PRO 2000 are naphthalene sulfonate polymers that bind to CD4 with nanomolar affinity and block binding of gp120. Both have activity against human immunodeficiency virus type 1 in H9 cells, peripheral blood mononuclear cells, and primary monocyte/macrophages, are synergistic with zidovudine, and do not inhibit tetanus toxoid-stimulated T-cell proliferation at anti-human immunodeficiency virus type 1 concentrations.

scholarly journals Cocaine Differentially Modulates Chemokine Production by Mononuclear Cells from Normal Donors and Human Immunodeficiency Virus Type 1-Infected Patients

2000 ◽  
Vol 7 (1) ◽  
pp. 96-100 ◽  
Author(s):  
Madhavan P. N. Nair ◽  
Kailash C. Chadha ◽  
Ross G. Hewitt ◽  
Supriya Mahajan ◽  
Ann Sweet ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Chemokine Production ◽  
Normal Peripheral Blood ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Earlier studies have supported a significant role for cocaine in the susceptibility to and the progression of human immunodeficiency virus type 1 (HIV-1) infection. Recently, several unique HIV-1 entry coreceptors (e.g., CCR5 and CCR3) and a trio of HIV-1-specific suppressor chemokines, namely, RANTES (regulated-upon-activation T expressed and secreted), macrophage inflammatory protein 1α (MIP-1α) and MIP-1β, were identified. Although cocaine has been linked to the immunopathogenesis of HIV-1 infection, the corresponding cellular and molecular mechanism(s) have not been well defined. We hypothesize that cocaine mediates these pathologic effects through the downregulation of HIV-1-suppressing chemokines and/or upregulating HIV-1 entry coreceptors in HIV-1-infected subjects, resulting in disease progression to AIDS. Our results show that cocaine selectively downregulates endogenous MIP-1β secretion by normal peripheral blood mononuclear cells (PBMC), while cocaine did not affect the MIP-1β production by PBMC from AIDS patients. Cocaine also selectively suppresses lipopolysaccharide-induced MIP-1β production by PBMC from HIV-infected patients. Further, cocaine significantly downregulates endogenous MIP-1β gene expression, while it upregulates HIV-1 entry coreceptor CCR5 by normal PBMC. These studies suggests a role for cocaine as a cofactor in the pathogenesis of HIV infection and support the premise that cocaine increases susceptibility to and progression of HIV-1 infection by inhibiting the synthesis of HIV-1 protective chemokines and/or upregulating the HIV-1 entry coreceptor, CCR5.

scholarly journals High Frequency of Syncytium-Inducing and CXCR4-Tropic Viruses among Human Immunodeficiency Virus Type 1 Subtype C-Infected Patients Receiving Antiretroviral Treatment

2003 ◽  
Vol 77 (13) ◽  
pp. 7682-7688 ◽  
Author(s):  
Elizabeth R. Johnston ◽  
Lynn S. Zijenah ◽  
Solomon Mutetwa ◽  
Rami Kantor ◽  
Chonticha Kittinunvorakoon ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Antiretroviral Treatment ◽  
Mononuclear Cells ◽  
Resistance Mutations ◽  
Subtype C ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) subtype C viruses have been found to almost exclusively use the chemokine receptor CCR5 as a coreceptor for entry, even in patients with advanced AIDS. We have characterized subtype C virus isolates from 28 patients from Harare, Zimbabwe, 20 of whom were receiving antiretroviral treatment. Virus from 10 of the treated patients induced syncytium formation (SI virus) when cultured with MT2 cells. Only non-syncytium-inducing (NSI) virus was cultured from the peripheral blood mononuclear cells of the eight patients who had not received treatment. The majority of these subtype C SI viruses were capable of using both CCR5 and CXCR4 as coreceptors for viral entry, and the consensus V3 loop sequences from the SI viruses displayed a high net charge compared to those of NSI viruses. While those on treatment had reverse transcriptase (RT) and protease mutations, there was no clear association between RT and protease drug resistance mutations and coreceptor tropism. These results suggest that CXCR4-tropic viruses are present within the quasispecies of patients infected with subtype C virus and that antiretroviral treatment may create an environment for the emergence of CXCR4 tropism.

Sign in / Sign up

Export Citation Format

Share Document