scholarly journals Different Mutational Pathways to CXCR4 Coreceptor Switch of CCR5-Using Simian-Human Immunodeficiency Virus

2008 ◽  
Vol 82 (11) ◽  
pp. 5653-5656 ◽  
Author(s):  
Siu-hong Ho ◽  
Nataliya Trunova ◽  
Agegnehu Gettie ◽  
James Blanchard ◽  
Cecilia Cheng-Mayer
Keyword(s):  
Human Immunodeficiency Virus ◽  
Lymph Node ◽  
Experimental System ◽  
V3 Loop ◽  
Infected Macaque ◽  
Immunodeficiency Virus ◽  
Coreceptor Switch ◽  
Cxcr4 Coreceptor ◽  
Functional Analyses

ABSTRACT We report here a second case of coreceptor switch in R5 simian-human immunodeficiency virus SF162P3N (SHIVSF162P3N)-infected macaque CA28, supporting the use of this experimental system to examine factors that drive the change in coreceptor preference in vivo. Virus recovered from CA28 plasma (SHIVCA28NP) used both CCR5 and CXCR4 for entry, but the virus recovered from lymph node (SHIVCA28NL) used CXCR4 almost exclusively. Sequence and functional analyses showed that mutations in the V3 loop that conferred CXCR4 usage in macaque CA28 differed from those described in the previously reported case, demonstrating divergent mutational pathways for change in the coreceptor preference of the R5 SHIVSF162P3N isolate in vivo.

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 Fitness Disadvantage of Transitional Intermediates Contributes to Dynamic Change in the Infecting-Virus Population during Coreceptor Switch in R5 Simian/Human Immunodeficiency Virus-Infected Macaques

2010 ◽  
Vol 84 (24) ◽  
pp. 12862-12871 ◽  
Author(s):  
Madina Shakirzyanova ◽  
Wuze Ren ◽  
Ke Zhuang ◽  
Silvana Tasca ◽  
Cecilia Cheng-Mayer
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dynamic Change ◽  
Virus Population ◽  
Immunodeficiency Virus ◽  
Coreceptor Switch ◽  
Disease Stages ◽  
Entry Efficiency ◽  
Made In

ABSTRACT Fitness disadvantage of the transitional intermediates compared to the initial R5 viruses has been suggested to constitute one of the blockades to coreceptor switching, explaining the late appearance of X4 viruses. Using a simian model for human immunodeficiency virus type 1 (HIV-1) coreceptor switching, we demonstrate in this study that similar molecular evolutionary pathways to coreceptor switch occur in more than one R5 simian/human immunodeficiency virus (SHIV)SF162P3N-infected macaque. In infected animals where multiple pathways for expansion or switch to CXCR4 coexist, fitness of the transitional intermediates in coreceptor usage efficiency influences their outgrowth and representation in the infecting virus population. Dualtropic and X4 viruses appear at different disease stages, but they have lower entry efficiency than the coexisting R5 strains, which may explain why they do not outcompete the R5 viruses. Similar observations were made in two infected macaques with coreceptor switch, providing in vivo evidence that fitness disadvantage is an obstacle to X4 emergence and expansion.

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 R5X4 Viruses Are Evolutionary, Functional, and Antigenic Intermediates in the Pathway of a Simian-Human Immunodeficiency Virus Coreceptor Switch

2008 ◽  
Vol 82 (14) ◽  
pp. 7089-7099 ◽  
Author(s):  
Silvana Tasca ◽  
Siu-Hong Ho ◽  
Cecilia Cheng-Mayer
Keyword(s):  
Human Immunodeficiency Virus ◽  
Intermediate Phase ◽  
Target Cells ◽  
V3 Loop ◽  
Cxcr4 Usage ◽  
Loop Sequence ◽  
Immunodeficiency Virus ◽  
Cd4 Binding Site ◽  
Coreceptor Switch ◽  
Switch Variant

ABSTRACT To examine the pathway of the coreceptor switching of CCR5-using (R5) virus to CXCR4-using (X4) virus in simian-human immunodeficiency virus SHIVSF162P3N-infected rhesus macaque BR24, analysis was performed on variants present at 20 weeks postinfection, the time when the signature gp120 V3 loop sequence of the X4 switch variant was first detected by PCR. Unexpectedly, circulating and tissue variants with His/Ile instead of the signature X4 V3 His/Arg insertions predominated at this time point. Phylogenetic analysis of the sequences of the C2 conserved region to the V5 variable loop of the envelope (Env) protein showed that viruses bearing HI insertions represented evolutionary intermediates between the parental SHIVSF162P3N and the final X4 HR switch variant. Functional analyses demonstrated that the HI variants were phenotypic intermediates as well, capable of using both CCR5 and CXCR4 for entry. However, the R5X4 intermediate virus entered CCR5-expressing target cells less efficiently than the parental R5 strain and was more sensitive to both CCR5 and CXCR4 inhibitors than either the parental R5 or the final X4 virus. It was also more sensitive than the parental R5 virus to antibody neutralization, especially to agents directed against the CD4 binding site, but not as sensitive as the late X4 virus. Significantly, the V3 loop sequence that determined CXCR4 use also conferred soluble CD4 neutralization sensitivity. Collectively, the data illustrate that, similar to human immunodeficiency virus type 1 (HIV-1) infection in individuals, the evolution from CCR5 to CXCR4 usage in BR24 transitions through an intermediate phase with reduced virus entry and coreceptor usage efficiencies. The data further support a model linking an open envelope gp120 conformation, better CD4 binding, and expansion to CXCR4 usage.

scholarly journals Envelope Glycoprotein Determinants of Increased Fusogenicity in a Pathogenic Simian-Human Immunodeficiency Virus (SHIV-KB9) Passaged In Vivo

2000 ◽  
Vol 74 (9) ◽  
pp. 4433-4440 ◽  
Author(s):  
Bijan Etemad-Moghadam ◽  
Ying Sun ◽  
Emma K. Nicholson ◽  
Mark Fernandes ◽  
Kwa Liou ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Receptor Binding ◽  
Chemokine Receptor ◽  
Envelope Glycoprotein ◽  
Syncytium Formation ◽  
V3 Loop ◽  
Gp41 Ectodomain ◽  
Immunodeficiency Virus

ABSTRACT Changes in the envelope glycoprotein ectodomains of a nonpathogenic simian-human immunodeficiency virus (SHIV-89.6) that was serially passaged in vivo have been shown to be responsible for the increased pathogenicity of the resulting virus, SHIV-KB9 (G. B. Karlsson, et al., J. Exp. Med. 188:1159–1171, 1998). The 12 amino acid changes in the envelope glycoprotein ectodomains resulted in increased chemokine receptor-binding and syncytium-forming abilities. Here we identify the envelope glycoprotein determinants of these properties. A single amino acid change in the gp120 third variable (V3) loop was both necessary and sufficient for the observed increase in the binding of the SHIV-KB9 gp120 glycoprotein to the CCR5 chemokine receptor. The increased syncytium-forming ability of SHIV-KB9 involved, in addition to the V3 loop change, changes in the second conserved (C2) region of gp120 (residue 225) and in the gp41 ectodomain (residues 564 and 567). The C2 and gp41 ectodomain changes influenced syncytium formation in a cooperative manner. Changes in the V1/V2 gp120 variable loops exerted a negative effect on syncytium formation and chemokine receptor binding, supporting a previously described role of these changes in immune evasion. The definition of the passage-associated changes that determine the efficiency of chemokine receptor binding and membrane fusogenicity will allow evaluation of the contribution of these properties to in vivo CD4-positive lymphocyte depletion.

scholarly journals CD4-Induced T-20 Binding to Human Immunodeficiency Virus Type 1 gp120 Blocks Interaction with the CXCR4 Coreceptor

2004 ◽  
Vol 78 (10) ◽  
pp. 5448-5457 ◽  
Author(s):  
Wen Yuan ◽  
Stewart Craig ◽  
Zhihai Si ◽  
Michael Farzan ◽  
Joseph Sodroski
Keyword(s):  
Human Immunodeficiency Virus ◽  
Membrane Fusion ◽  
Heptad Repeat ◽  
V3 Loop ◽  
Repeat Region ◽  
Coreceptor Binding ◽  
Immunodeficiency Virus ◽  
Cxcr4 Coreceptor ◽  
Hiv 1

ABSTRACT The synthetic peptide T-20, which corresponds to a sequence within the C-terminal heptad repeat region (HR2) of the human immunodeficiency virus type 1 (HIV-1) gp41 envelope glycoprotein, potently inhibits viral membrane fusion and entry. Although T-20 is thought to bind the N-terminal heptad repeat region (HR1) of gp41 and interfere with gp41 conformational changes required for membrane fusion, coreceptor specificity determined by the V3 loop of gp120 strongly influences the sensitivity of HIV-1 variants to T-20. Here, we show that T-20 binds to the gp120 glycoproteins of HIV-1 isolates that utilize CXCR4 as a coreceptor in a manner determined by the sequences of the gp120 V3 loop. T-20 binding to gp120 was enhanced in the presence of soluble CD4. Analysis of T-20 binding to gp120 mutants with variable loop deletions and the reciprocal competition of T-20 and particular anti-gp120 antibodies suggested that T-20 interacts with a gp120 region near the base of the V3 loop. Consistent with the involvement of this region in coreceptor binding, T-20 was able to block the interaction of gp120-CD4 complexes with the CXCR4 coreceptor. These results help to explain the increased sensitivity of CXCR4-specific HIV-1 isolates to the T-20 peptide. Interactions between the gp41 HR2 region and coreceptor-binding regions of gp120 may also play a role in the function of the HIV-1 envelope glycoproteins.

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 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 Coreceptor Tropism in Human Immunodeficiency Virus Type 1 Subtype D: High Prevalence of CXCR4 Tropism and Heterogeneous Composition of Viral Populations

2007 ◽  
Vol 81 (15) ◽  
pp. 7885-7893 ◽  
Author(s):  
Wei Huang ◽  
Susan H. Eshleman ◽  
Jonathan Toma ◽  
Signe Fransen ◽  
Eric Stawiski ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
V3 Loop ◽  
Coreceptor Tropism ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Cxcr4 Coreceptor ◽  
Subtype A ◽  
Hiv 1

ABSTRACT In human immunodeficiency virus type 1 (HIV-1) subtype B, CXCR4 coreceptor use ranges from ∼20% in early infection to ∼50% in advanced disease. Coreceptor use by non-subtype B HIV is less well characterized. We studied coreceptor tropism of subtype A and D HIV-1 collected from 68 pregnant, antiretroviral drug-naive Ugandan women (HIVNET 012 trial). None of 33 subtype A or 10 A/D-recombinant viruses used the CXCR4 coreceptor. In contrast, nine (36%) of 25 subtype D viruses used both CXCR4 and CCR5 coreceptors. Clonal analyses of the nine subtype D samples with dual or mixed tropism revealed heterogeneous viral populations comprised of X4-, R5-, and dual-tropic HIV-1 variants. In five of the six samples with dual-tropic strains, V3 loop sequences of dual-tropic clones were identical to those of cocirculating R5-tropic clones, indicating the presence of CXCR4 tropism determinants outside of the V3 loop. These dual-tropic variants with R5-tropic-like V3 loops, which we designated “dual-R,” use CCR5 much more efficiently than CXCR4, in contrast to dual-tropic clones with X4-tropic-like V3 loops (“dual-X”). These observations have implications for pathogenesis and treatment of subtype D-infected individuals, for the association between V3 sequence and coreceptor tropism phenotype, and for understanding potential mechanisms of evolution from exclusive CCR5 use to efficient CXCR4 use by subtype D HIV-1.

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