Resistance pathways of human immunodeficiency virus type 1 against the combination of zidovudine and lamivudine

A better understanding of human immunodeficiency virus type 1 drug-resistance evolution under the selective pressure of combination treatment is important for the design of long-term effective treatment strategies. We applied Bayesian network learning to sequences from patients treated with the reverse transcriptase inhibitor combination of zidovudine (AZT) and lamivudine (3TC) to identify the role of many treatment-selected mutations in the development of resistance. Based on the Bayesian network structure, an in vivo fitness landscape was built, reflecting the necessary selective pressure under treatment, to evolve naive sequences to sequences obtained from patients treated with the combination. This landscape, combined with an evolutionary model, was used to predict resistance evolution in longitudinal sequence pairs. In our analysis, mutations 41L, 70R, 184V and 215F/Y were identified as major resistance mutations to the combination of AZT and 3TC, as they were associated directly with treatment experience. The network also suggested a possible role in resistance development for a number of novel mutations. Estimated fitness, using the landscape, correlated significantly with in vitro resistance phenotype in genotype–phenotype pairs (R 2=0.70). Variation in predicted evolution under selective pressure correlated significantly with observed in vivo evolution during AZT plus 3CT treatment. In conclusion, we confirmed current knowledge on resistance development to the combination of AZT and 3CT, but additional novel mutations were identified. Moreover, a model to predict resistance evolution during AZT and 3CT treatment has been built and validated.

Download Full-text

Independent fluctuation of human immunodeficiency virus type 1 rev and gp41 quasispecies in vivo.

Journal of Virology ◽

10.1128/jvi.65.8.4502-4507.1991 ◽

1991 ◽

Vol 65 (8) ◽

pp. 4502-4507 ◽

Cited By ~ 24

Author(s):

L P Martins ◽

N Chenciner ◽

B Asjö ◽

A Meyerhans ◽

S Wain-Hobson

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Immunodeficiency Virus

Download Full-text

Mutational analysis of human immunodeficiency virus type 1 (HIV-1) accessory genes: requirement of a site in the nef gene for HIV-1 replication in activated CD4+ T cells in vitro and in vivo.

Journal of Virology ◽

10.1128/jvi.71.11.8456-8466.1997 ◽

1997 ◽

Vol 71 (11) ◽

pp. 8456-8466 ◽

Cited By ~ 36

Author(s):

Y Kawano ◽

Y Tanaka ◽

N Misawa ◽

R Tanaka ◽

J I Kira ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Human Immunodeficiency Virus Type ◽

Mutational Analysis ◽

Immunodeficiency Virus ◽

A Site ◽

Hiv 1

Download Full-text

Allogeneic leukocytes but not therapeutic blood elements induce reactivation and dissemination of latent human immunodeficiency virus type 1 infection: implications for transfusion support of infected patients

Blood ◽

10.1182/blood.v80.8.2128.2128 ◽

1992 ◽

Vol 80 (8) ◽

pp. 2128-2135 ◽

Cited By ~ 74

Author(s):

MP Busch ◽

TH Lee ◽

J Heitman

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Blood Components ◽

Route Of Transmission ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Donor Lymphocytes

Abstract Various immunologic stimuli and heterologous viral regulatory elements have been shown to increase susceptibility to, and replication of, human immunodeficiency virus type 1 (HIV-1) in lymphocytes and monocytes in vitro. Transfusion of allogeneic blood components from heterologous donors constitutes a profound immunologic stimulus to the recipient, in addition to being a potential route of transmission of lymphotropic viral infections. To investigate the hypothesis that transfusions, and particularly those containing leukocytes, activate HIV-1 replication in infected recipient cells, we cocultured peripheral blood mononuclear cells (PBMC) from three anti-HIV-1-positive individuals with allogeneic donor PBMC, as well as partially purified populations of donor lymphocytes, monocytes, granulocytes, platelets, and red blood cells (RBC) and allogeneic cell-free plasma. Allogeneic PBMC induced a dose-related activation of HIV-1 expression in in vivo infected cells, followed by dissemination of HIV-1 to previously uninfected patient cells. Activation of HIV-1 replication was observed with donor lymphocytes, monocytes, and granulocytes, whereas no effect was seen with leukocyte-depleted RBC, platelets, or plasma (ie, therapeutic blood constituents). Allogeneic donor PBMC were also shown to upregulate HIV-1 expression in a “latently” infected cell line, and to increase susceptibility of heterologous donor PBMC to acute HIV-1 infection. Studies should be performed to evaluate whether transfusions of leukocyte-containing blood components accelerate HIV-1 dissemination and disease progression in vivo. If so, HIV-1-infected patients should be transfused as infrequently as possible and leukocyte-depleted (filtered) blood components should be used to avoid this complication.

Download Full-text

Recruitment of Antigen-Presenting Cells to the Site of Inoculation and Augmentation of Human Immunodeficiency Virus Type 1 DNA Vaccine Immunogenicity by In Vivo Electroporation

Journal of Virology ◽

10.1128/jvi.02564-07 ◽

2008 ◽

Vol 82 (11) ◽

pp. 5643-5649 ◽

Cited By ~ 84

Author(s):

Jinyan Liu ◽

Rune Kjeken ◽

Iacob Mathiesen ◽

Dan H. Barouch

Keyword(s):

Human Immunodeficiency Virus ◽

Dna Vaccine ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Antigen Presenting Cells ◽

In Vivo Electroporation ◽

Immunodeficiency Virus ◽

Antigen Presenting

ABSTRACT In vivo electroporation (EP) has been shown to augment the immunogenicity of plasmid DNA vaccines, but its mechanism of action has not been fully characterized. In this study, we show that in vivo EP augmented cellular and humoral immune responses to a human immunodeficiency virus type 1 Env DNA vaccine in mice and allowed a 10-fold reduction in vaccine dose. This enhancement was durable for over 6 months, and re-exposure to antigen resulted in anamnestic effector and central memory CD8+ T-lymphocyte responses. Interestingly, in vivo EP also recruited large mixed cellular inflammatory infiltrates to the site of inoculation. These infiltrates contained 45-fold-increased numbers of macrophages and 77-fold-increased numbers of dendritic cells as well as 2- to 6-fold-increased numbers of B and T lymphocytes compared to infiltrates following DNA vaccination alone. These data suggest that recruiting inflammatory cells, including antigen-presenting cells (APCs), to the site of antigen production substantially improves the immunogenicity of DNA vaccines. Combining in vivo EP with plasmid chemokine adjuvants that similarly recruited APCs to the injection site, however, did not result in synergy.

Download Full-text

The Interaction of Vpr with Uracil DNA Glycosylase Modulates the Human Immunodeficiency Virus Type 1 In Vivo Mutation Rate

Journal of Virology ◽

10.1128/jvi.74.15.7039-7047.2000 ◽

2000 ◽

Vol 74 (15) ◽

pp. 7039-7047 ◽

Cited By ~ 126

Author(s):

Louis M. Mansky ◽

Sandra Preveral ◽

Luc Selig ◽

Richard Benarous ◽

Serge Benichou

Keyword(s):

Human Immunodeficiency Virus ◽

Mutation Rate ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Dna Glycosylase ◽

Uracil Dna Glycosylase ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The Vpr protein of human immunodeficiency virus type 1 (HIV-1) influences the in vivo mutation rate of the virus. Since Vpr interacts with a cellular protein implicated in the DNA repair process, uracil DNA glycosylase (UNG), we have explored the contribution of this interaction to the mutation rate of HIV-1. Single-amino-acid variants of Vpr were characterized for their differential UNG-binding properties and used to trans complement vpr null mutant HIV-1. A striking correlation was established between the abilities of Vpr to interact with UNG and to influence the HIV-1 mutation rate. We demonstrate that Vpr incorporation into virus particles is required to influence the in vivo mutation rate and to mediate virion packaging of the nuclear form of UNG. The recruitment of UNG into virions indicates a mechanism for how Vpr can influence reverse transcription accuracy. Our data suggest that distinct mechanisms evolved in primate and nonprimate lentiviruses to reconcile uracil misincorporation into lentiviral DNA.

Download Full-text

In vivo characteristics of human immunodeficiency virus type 1 intersubtype recombination: determination of hot spots and correlation with sequence similarity

Journal of General Virology ◽

10.1099/vir.0.19180-0 ◽

2003 ◽

Vol 84 (10) ◽

pp. 2715-2722 ◽

Cited By ~ 51

Author(s):

Gkikas Magiorkinis ◽

Dimitrios Paraskevis ◽

Anne-Mieke Vandamme ◽

Emmanouil Magiorkinis ◽

Vana Sypsa ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Recombination Frequency ◽

Sequence Similarity ◽

Virus Species ◽

Immunodeficiency Virus ◽

Hiv 1

Recombination plays a pivotal role in the evolutionary process of many different virus species, including retroviruses. Analysis of all human immunodeficiency virus type 1 (HIV-1) intersubtype recombinants revealed that they are more complex than described initially. Recombination frequency is higher within certain genomic regions, such as partial reverse transcriptase (RT), vif/vpr, the first exons of tat/rev, vpu and gp41. A direct correlation was observed between recombination frequency and sequence similarity across the HIV-1 genome, indicating that sufficient sequence similarity is required upstream of the recombination breakpoint. This finding suggests that recombination in vivo may occur preferentially during reverse transcription through the strand displacement-assimilation model rather than the copy-choice model.

Download Full-text