Clinical Significance and Characterization of AZT-Resistant Strains of HIV-1

A number of laboratories have now independently confirmed that zidovudine (AZT)-resistant strains of human immunodeficiency virus type 1 (HIV-1) may be isolated from patients undergoing prolonged therapy with this drug. In certain instances, such drug-resistant viral isolates have been obtained from patients with clinical acquired immune deficiency syndrome (AIDS), while in others, isolation of drug-resistant strains has been achieved in the case of HIV seropositive, asymptomatic subjects. Most of the evidence points to a series of mutations within the polymerase gene of HIV-1, which encodes viral reverse transcriptase, as being responsible for development of the drug-resistant phenotype. It further appears that over 50% of patients treated with AZT for periods longer than six months are likely to yield drug-resistant strains of HIV-1 in their circulation. Furthermore, the development of drug resistance soon after initiation of AZT therapy may potentially be correlated with the likelihood of AZT treatment failure. In several instances, cross resistance has been observed between AZT and other nucleosides being considered for potential therapy of HIV-1-associated disease.

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Synthesis and evaluation of potent human immunodeficiency virus 1 protease inhibitors with epimeric isopropanol as novel P1′ ligands

Future Medicinal Chemistry ◽

10.4155/fmc-2019-0331 ◽

2020 ◽

Vol 12 (9) ◽

pp. 775-794 ◽

Cited By ~ 1

Author(s):

Mei Zhu ◽

Ling Ma ◽

Biao Dong ◽

Guoning Zhang ◽

Juxian Wang ◽

...

Keyword(s):

Protease Inhibitors ◽

Design Strategy ◽

Drug Resistant ◽

Inhibition Activity ◽

Protease Enzyme ◽

Immunodeficiency Virus ◽

Resistant Strains ◽

Backbone Atoms ◽

Drug Resistant Strains ◽

Hiv 1

Aim: HIV-1 protease inhibitors regimens suffered from a number of drawbacks, among which, the most egregious issue was the growing emergence of drug-resistant strains. Materials & methods: The design strategy of maximizing the protease active site interactions with the inhibitor, especially promoting extensive hydrogen bonding with the protein backbone atoms, might be in favor of combating drug resistance. A series of HIV-1 protease inhibitors that incorporated enantiomeric isopropanols as the P1′ ligands in combination with phenols as the P2 ligands were reported herein. Results: A number of inhibitors displayed potent protease enzyme inhibition activity. In particular, inhibitor 14c showed comparable potency as darunavir with IC50 value of 1.91 nM and activity against darunavir-resistant HIV-1 variants. Conclusion: The new kind of HIV-1 protease inhibitors deserves further study.

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The origin of acquired immune deficiency syndrome: Darwinian or Lamarckian?

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2001.0864 ◽

2001 ◽

Vol 356 (1410) ◽

pp. 877-887 ◽

Cited By ~ 6

Author(s):

Tom Burr ◽

J. M. Hyman ◽

Gerald Myers

Keyword(s):

Immune Deficiency ◽

Simulated Data ◽

Immune Deficiency Syndrome ◽

Acquired Immune Deficiency Syndrome ◽

Deficiency Syndrome ◽

Darwinian Evolution ◽

Immunodeficiency Virus ◽

Acquired Immune Deficiency ◽

Hiv 1

The subtypes of human immunodeficiency virus type 1 (HIV–1) group M exhibit a remarkable similarity in their between–subtype distances, which we refer to as high synchrony. The shape of the phylogenetic tree of these subtypes is referred to as a sunburst to distinguish it from a simple star phylogeny. Neither a sunburst pattern nor a comparable degree of symmetry is seen in a natural process such as in feline immunodeficiency virus evolution. We therefore have undertaken forward–process simulation studies employing coalescent theory to investigate whether such highly synchronized subtypes could be readily produced by natural Darwinian evolution. The forward model includes both classical (macro) and molecular (micro) epidemiological components. HIV–1 group M subtype synchrony is quantified using the standard deviation of the between–subtype distances and the average of the within–subtype distances. Highly synchronized subtypes and a sunburst phylogeny are not observed in our simulated data, leading to the conclusion that a quasi–Lamarckian, punctuated event occurred. The natural transfer theory for the origin of human acquired immune deficiency syndrome (AIDS) cannot easily be reconciled with these findings and it is as if a recent non–Darwinian process took place coincident with the rise of AIDS in Africa.

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In Vitro Antiviral Activity and Cross-Resistance Profile of PL-100, a Novel Protease Inhibitor of Human Immunodeficiency Virus Type 1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00149-07 ◽

2007 ◽

Vol 51 (11) ◽

pp. 4036-4043 ◽

Cited By ~ 21

Author(s):

Serge Dandache ◽

Guy Sévigny ◽

Jocelyn Yelle ◽

Brent R. Stranix ◽

Neil Parkin ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Antiviral Activity ◽

Highly Active Antiretroviral Therapy ◽

Cross Resistance ◽

Drug Resistant ◽

Resistance Profile ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Despite the success of highly active antiretroviral therapy, the current emergence and spread of drug-resistant variants of human immunodeficiency virus (HIV) stress the need for new inhibitors with distinct properties. We designed, produced, and screened a library of compounds based on an original l-lysine scaffold for their potentials as HIV type 1 (HIV-1) protease inhibitors (PI). One candidate compound, PL-100, emerged as a specific and noncytotoxic PI that exhibited potent inhibition of HIV-1 protease and viral replication in vitro (Ki , ∼36 pM, and 50% effective concentration [EC50], ∼16 nM, respectively). To confirm that PL-100 possessed a favorable resistance profile, we performed a cross-resistance study using a panel of 63 viral strains from PI-experienced patients selected for the presence of primary PI mutations known to confer resistance to multiple PIs now in clinical use. The results showed that PL-100 retained excellent antiviral activity against almost all of these PI-resistant viruses and that its performance in this regard was superior to those of atazanavir, amprenavir, indinavir, lopinavir, nelfinavir, and saquinavir. In almost every case, the increase in the EC50 for PL-100 observed with viruses containing multiple mutations in protease was far less than that obtained with the other drugs tested. These data underscore the potential for PL-100 to be used in the treatment of drug-resistant HIV disease and argue for its further development.

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Differential Effects of Interleukin-13 on Cytomegalovirus and Human Immunodeficiency Virus Infection in Human Alveolar Macrophages

Blood ◽

10.1182/blood.v89.9.3443 ◽

1997 ◽

Vol 89 (9) ◽

pp. 3443-3450 ◽

Cited By ~ 8

Author(s):

William C. Hatch ◽

Andrew R. Freedman ◽

Deborah M. Boldt-Houle ◽

Jerome E. Groopman ◽

Ernest F. Terwilliger

Keyword(s):

Human Immunodeficiency Virus ◽

Alveolar Macrophages ◽

Immune Deficiency Syndrome ◽

Deficiency Syndrome ◽

Dependent Manner ◽

Principal Line ◽

Differential Effects ◽

Interleukin 13 ◽

Immunodeficiency Virus ◽

Hiv 1

Abstract Alveolar macrophages, which form a principal line of defense against a variety of pulmonary pathogens, may themselves be infected by viruses like human immunodeficiency virus-1 (HIV-1), which impair their defensive functions. Interleukin-13 (IL-13), a multifunctional cytokine, has been considered for therapeutic use based on its potent inhibition of HIV-1 in these cells. We have further examined the effects of IL-13 on alveolar macrophages under conditions that reflect those seen in acquired immune deficiency syndrome, where this cell type is often infected by the opportunistic pathogen human cytomegalovirus (HCMV). Alveolar macrophages exposed to both HCMV and HIV-1 consistently exhibited higher levels of HIV-1 replication than cells exposed to HIV-1 alone. HIV-1 production was strongly suppressed in alveolar macrophages treated with IL-13 regardless of whether or not the cultures were coinfected with HCMV. However, IL-13 treatment markedly enhanced the expression of HCMV in otherwise latently infected macrophages in a dose dependent manner. These unexpected differential effects of IL-13 on host-virus interactions are important considerations in guiding its potential therapeutic applications.

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The earliest cases of human immunodeficiency virus type 1 group M in Congo-Kinshasa, Rwanda and Burundi and the origin of acquired immune deficiency syndrome

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2001.0876 ◽

2001 ◽

Vol 356 (1410) ◽

pp. 923-925 ◽

Cited By ~ 10

Author(s):

Daniel Vangroenweghe

Keyword(s):

Immune Deficiency ◽

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Immune Deficiency Syndrome ◽

Acquired Immune Deficiency Syndrome ◽

Deficiency Syndrome ◽

Immunodeficiency Virus ◽

Acquired Immune Deficiency ◽

Hiv 1

The early cases of acquired immune deficiency syndrome and human immunodeficiency virus type 1 (HIV–1) infection in the 1960s and 1970s in Congo–Kinshasa (Zaire), Rwanda and Burundi are reviewed. These countries appear to be the source of the HIV–1 group M epidemic, which then spread outwards to neighbouring Tanzania and Uganda in the east, and Congo–Brazzaville in the west. Further spread to Haiti and onwards to the USA can be explained by the hundreds of single men from Haiti who participated in the UNESCO educational programme in the Congo between 1960 and 1975.

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