scholarly journals Human Immunodeficiency Virus Type 1 IIIB Selected for Replication In Vivo Exhibits Increased Envelope Glycoproteins in Virions without Alteration in Coreceptor Usage: Separation of In Vivo Replication from Macrophage Tropism

2001 ◽  
Vol 75 (18) ◽  
pp. 8498-8506 ◽  
Author(s):  
Eric D. Miller ◽  
Karen M. Duus ◽  
Michael Townsend ◽  
Yanjie Yi ◽  
Ronald Collman ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
V3 Loop ◽  
Coreceptor Usage ◽  
Laboratory Worker ◽  
Immunodeficiency Virus ◽  
Replication Activity ◽  
Hiv 1 ◽  
Selection Of

ABSTRACT Analysis of viral replication and pathogenicity after in vivo selection of human immunodeficiency virus type 1 (HIV-1) attenuated in vitro will help to define the functions involved in replication and pathogenesis in vivo. Using the SCID-hu Thy/Liv mouse and human fetal thymus organ culture as in vivo models, we previously defined HIV-1env determinants (HXB2/LW) which were reverted for replication in vivo (L. Su et al., Virology 227:46–52, 1997). In this study, we examined the replication of four highly related HIV-1 clones directly derived from Lai/IIIB or after selection in vivo to investigate the envelope gp120 determinants associated with replication in macrophages and in the thymus models in vivo. The LW/C clone derived from the IIIB-infected laboratory worker and HXB2/LW both efficiently infected monocyte-derived macrophages (MDM) and the human thymus. Although the laboratory worker (LW) isolates showed altered tropism from IIIB, they still predominantly used CXCR4 as coreceptors for infecting peripheral blood mononuclear cells, macrophages, and the thymus. Interestingly, a single amino acid mutation in the V3 loop associated with resistance to neutralizing antibodies was also essential for the replication activity of the LW virus in the thymus models but not for its activity in infecting MDM. The LW virions were equally sensitive to a CXCR4 antagonist. We further demonstrated that the LW HIV-1 isolate selected in vivo produced more infectious viral particles that contained higher levels of the Env protein gp120. Thus, selection of the laboratory-attenuated Lai/IIIB isolate in vivo leads to altered tropism but not coreceptor usage of the virus. The acquired replication activity in vivo is correlated with an early A-to-T mutation in the V3 loop and increased virion association of HIV-1 Env gp120, but it is genetically separable from the acquired replication activity in macrophages.

scholarly journals Reversal of Human Immunodeficiency Virus Type 1 IIIB to a Neutralization-Resistant Phenotype in an Accidentally Infected Laboratory Worker with a Progressive Clinical Course

2001 ◽  
Vol 75 (5) ◽  
pp. 2246-2252 ◽  
Author(s):  
Tim Beaumont ◽  
Ad van Nuenen ◽  
Silvia Broersen ◽  
William A. Blattner ◽  
Vladimir V. Lukashov ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Envelope Gene ◽  
Nucleotide Substitutions ◽  
Laboratory Worker ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The role of humoral immunity in controlling human immunodeficiency virus type 1 (HIV-1) is still controversial. The resistance of primary HIV-1 variants to neutralization by antibodies, sera from HIV-1-infected patients, and soluble CD4 protein has been suggested to be a prerequisite for the virus to establish persistence in vivo. To further test this hypothesis, we studied the neutralization sensitivity of two IIIB/LAV variants that were isolated from a laboratory worker who accidentally was infected with the T-cell-line-adapted neutralization-sensitive IIIB isolate. Compared to the original virus in the inoculum, the reisolated viruses showed an increased resistance to neutralization over time. The ratio of nonsynonymous to synonymous nucleotide substitutions in the envelope gene pointed to strong positive selection. The emergence of neutralization-resistant HIV preceded disease development in this laboratory worker. Our results imply that the neutralization resistance of primary HIV may indeed be considered an escape mechanism from humoral immune control.

scholarly journals In Vivo Emergence of Vicriviroc Resistance in a Human Immunodeficiency Virus Type 1 Subtype C-Infected Subject

2008 ◽  
Vol 82 (16) ◽  
pp. 8210-8214 ◽  
Author(s):  
Athe M. N. Tsibris ◽  
Manish Sagar ◽  
Roy M. Gulick ◽  
Zhaohui Su ◽  
Michael Hughes ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Ccr5 Antagonist ◽  
V3 Loop ◽  
Subtype C ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Little is known about the in vivo development of resistance to human immunodeficiency virus type 1 (HIV-1) CCR5 antagonists. We studied 29 subjects with virologic failure from a phase IIb study of the CCR5 antagonist vicriviroc (VCV) and identified one individual with HIV-1 subtype C who developed VCV resistance. Studies with chimeric envelopes demonstrated that changes within the V3 loop were sufficient to confer VCV resistance. Resistant virus showed VCV-enhanced replication, cross-resistance to another CCR5 antagonist, TAK779, and increased sensitivity to aminooxypentane-RANTES and the CCR5 monoclonal antibody HGS004. Pretreatment V3 loop sequences reemerged following VCV discontinuation, implying that VCV resistance has associated fitness costs.

scholarly journals T-cell line adaptation of human immunodeficiency virus type 1 strain SF162: effects on envelope, vpu and macrophage-tropism

2000 ◽  
Vol 81 (12) ◽  
pp. 2899-2904 ◽  
Author(s):  
Nathalie Dejucq ◽  
Graham Simmons ◽  
Paul R. Clapham
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Cell Line ◽  
Human Immunodeficiency Virus Type ◽  
V3 Loop ◽  
Macrophage Tropism ◽  
Immunodeficiency Virus ◽  
Hiv 1

Changes in co-receptor-use by human immunodeficiency virus type 1 (HIV-1) strains are relatively rare in vivo. Here we describe two variants derived from the CCR5-using strain SF162, selected for replication in the C8166 T-cell line. Amino acid substitutions in the V3 loop conferred CXCR4-use; however, the loss of macrophage-tropism by one variant was due to a single mutation in the start codon of vpu. We discuss how V3 loop and vpu mutations acquired by replication in T-cell lines in vitro correlate with similar changes reported for primary isolates and HIV-1 sequences in vivo.

scholarly journals Heterogeneous Spectrum of Coreceptor Usage among Variants within a Dualtropic Human Immunodeficiency Virus Type 1 Primary-Isolate Quasispecies

2000 ◽  
Vol 74 (21) ◽  
pp. 10229-10235 ◽  
Author(s):  
Anjali Singh ◽  
Ronald G. Collman
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Late Stage ◽  
Primary Isolate ◽  
Coreceptor Usage ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) variants that use the coreceptor CCR5 for entry (R5; macrophage tropic) predominate in early infection, while variants that use CXCR4 emerge during disease progression. Some late-stage variants use CXCR4 alone (X4; T-cell tropic), while others use both CXCR4 and CCR5 (R5X4; dualtropic). It has been proposed that dualtropic R5X4 strains are intermediates in the evolution from R5 to X4, and we hypothesized that a dualtropic primary-isolate quasispecies might contain variants that represent the spectrum of coreceptor use in vivo. We generated a panel of 35 functional full-length env clones from the primary-isolate quasispecies of a dualtropic prototype strain, HIV-1 89.6PI. Thirty of the functional env clones (86%) were R5X4, four (11%) were R5, and one (3%) was predominantly X4. V3 to V5 sequences did not reveal clustering by coreceptor usage, and no specific sequence motif or V3 charge pattern corresponded to coreceptor utilization. Complete sequencing of seven functionally divergent Env proteins revealed ≥98.7% homology and conservation of structurally important domains. Chimeras between the R5X4 89.6 prototype and an R5 variant indicated that multiple regions contributed to the use of CXCR4, while chimeras with the X4 variant implicated a single residue in V4 in CCR5 use. These results confirm, at the molecular level, both that dualtropic variants are a predominant component of late-stage syncytium-inducing isolates and that variants restricted to each coreceptor coexist with dualtropic species in vivo. Coreceptor-restricted minority variants may reflect residual R5 species from earlier in disease as well as emerging X4 variants.

scholarly journals 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 ◽  
1992 ◽  
Vol 80 (8) ◽  
pp. 2128-2135 ◽  
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.

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

2000 ◽  
Vol 74 (15) ◽  
pp. 7039-7047 ◽  
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.

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

2003 ◽  
Vol 84 (10) ◽  
pp. 2715-2722 ◽  
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.

scholarly journals X4 Human Immunodeficiency Virus Type 1 gp120 Down-Modulates Expression and Immunogenicity of Codelivered Antigens

2009 ◽  
Vol 83 (21) ◽  
pp. 10941-10950 ◽  
Author(s):  
Avi-Hai Hovav ◽  
Michael Santosuosso ◽  
Maytal Bivas-Benita ◽  
Andre Plair ◽  
Alex Cheng ◽  
...  
Keyword(s):  
Immune Response ◽  
Human Immunodeficiency Virus ◽  
Antigen Presentation ◽  
Antigen Expression ◽  
V3 Loop ◽  
Humoral Immune ◽  
Immunodeficiency Virus ◽  
Aids Vaccines ◽  
Hiv 1

ABSTRACT In order to increase the immune breadth of human immunodeficiency virus (HIV) vaccines, strategies such as immunization with several HIV antigens or centralized immunogens have been examined. HIV-1 gp120 protein is a major immunogen of HIV and has been routinely considered for inclusion in both present and future AIDS vaccines. However, recent studies proposed that gp120 interferes with the generation of immune response to codelivered antigens. Here, we investigate whether coimmunization with plasmid-encoded gp120 alters the immune response to other coadministered plasmid encoded antigens such as luciferase or ovalbumin in a mouse model. We found that the presence of gp120 leads to a significant reduction in the expression level of the codelivered antigen in vivo. Antigen presentation by antigen-presenting cells was also reduced and resulted in the induction of weak antigen-specific cellular and humoral immune responses. Importantly, gp120-mediated immune interference was observed after administration of the plasmids at the same or at distinct locations. To characterize the region in gp120 mediating these effects, we used plasmid constructs encoding gp120 that lacks the V1V2 loops (ΔV1V2) or the V3 loop (ΔV3). After immunization, the ΔV1V2, but not the ΔV3 construct, was able to reduce antigen expression, antigen presentation, and subsequently the immunogenicity of the codelivered antigen. The V3 loop dependence of this phenomenon seems to be limited to V3 loops known to interact with the CXCR4 molecule but not with CCR5. Our study presents a novel mechanism by which HIV-1 gp120 interferes with the immune response against coadministered antigen in a polyvalent vaccine preparation.

scholarly journals Selective Excision of AZTMP by Drug-Resistant Human Immunodeficiency Virus Reverse Transcriptase

2001 ◽  
Vol 75 (10) ◽  
pp. 4832-4842 ◽  
Author(s):  
Paul L. Boyer ◽  
Stefan G. Sarafianos ◽  
Edward Arnold ◽  
Stephen H. Hughes
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Nucleoside Analogs ◽  
Azido Group ◽  
Resistance Mutations ◽  
Immunodeficiency Virus ◽  
Azt Resistance ◽  
Hiv 1

ABSTRACT Two distinct mechanisms can be envisioned for resistance of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) to nucleoside analogs: one in which the mutations interfere with the ability of HIV-1 RT to incorporate the analog, and the other in which the mutations enhance the excision of the analog after it has been incorporated. It has been clear for some time that there are mutations that selectively interfere with the incorporation of nucleoside analogs; however, it has only recently been proposed that zidovudine (AZT) resistance can involve the excision of the nucleoside analog after it has been incorporated into viral DNA. Although this proposal resolves some important issues, it leaves some questions unanswered. In particular, how do the AZT resistance mutations enhance excision, and what mechanism(s) causes the excision reaction to be relatively specific for AZT? We have used both structural and biochemical data to develop a model. In this model, several of the mutations associated with AZT resistance act primarily to enhance the binding of ATP, which is the most likely pyrophosphate donor in the in vivo excision reaction. The AZT resistance mutations serve to increase the affinity of RT for ATP so that, at physiological ATP concentrations, excision is reasonably efficient. So far as we can determine, the specificity of the excision reaction for an AZT-terminated primer is not due to the mutations that confer resistance, but depends instead on the structure of the region around the HIV-1 RT polymerase active site and on its interactions with the azido group of AZT. Steric constraints involving the azido group cause the end of an AZT 5′-monophosphate-terminated primer to preferentially reside at the nucleotide binding site, which favors excision.

Sign in / Sign up

Export Citation Format

Share Document