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Opalka D, Pessi A, Bianchi E, Ciliberto G, Schleif W, McElhaugh M, Danzeisen R, Geleziunas R, Miller M, Eckert DM, Bramhill D, Joyce J, Cook J, Magilton W, Shiver J, Emini E, Esser MTAnalysis of the HIV-1 gp41 specific immune response using a multiplexed antibody detection assay. J. Immunol. Methods 2004;287(1-2):49-65

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

A fluorescence-based, multiplexed, antibody-binding and mapping assay was developed to characterize antibody responses in HIV-1-infected individuals to the ectodomain of the HIV-1 gp41 envelope glycoprotein. The antigen panel included intact recombinant gp41, the fusion peptide region, the polar region, the N-heptad region, the C-heptad region as well as overlapping epitopes in the 2F5 and 4E10 monoclonal antibody-binding regions. The panel included both native and constrained peptides specifically designed to mimic putative gp41 prefusion and fusion intermediates. The results of these analyses revealed a broad pattern of immune responses against the test antigens, suggesting that none of these gp41 regions are immunologically silent. The HIV-1-positive sera were also evaluated using infectivity inhibition assays. No correlation was evident between the breadth or magnitude of specific anti-gp41 reactivities and virus neutralization potency. These evaluations demonstrated the substantial potential of the multiplexed antibody binding and mapping assay for rapid and sensitive analysis of complex antibody responses.

Huang CC, Venturi M, Majeed S, Moore MJ, Phogat S, Zhang MY, Dimitrov DS, Hendrickson WA, Robinson J, Sodroski J, Wyatt R, Choe H, Farzan M, Kwong PDStructural basis of tyrosine sulfation and VH-gene usage in antibodies that recognize the HIV type 1 coreceptor-binding site on gp120. Proc. Natl. Acad. Sci. U.S.A. 2004;101(9):2706-11

Abstract & Topics (Click to display abstract, topics and IAVI Projects)     FREE PMC ARTICLE

The conserved surface of the HIV-1 gp120 envelope glycoprotein that binds to the HIV-1 coreceptor is protected from humoral recognition by multiple layers of camouflage. Here we present sequence and genomic analyses for 12 antibodies that pierce these defenses and determine the crystal structures of 5. The data reveal mechanisms and atomic-level details for three unusual immune features: posttranslational mimicry of coreceptor by tyrosine sulfation of antibody, an alternative molecular mechanism controlling such sulfation, and highly selective V(H)-gene usage. When confronted by extraordinary viral defenses, the immune system unveils novel adaptive capabilities, with tyrosine sulfation enhancing the vocabulary of antigen recognition.

Negri DR, Baroncelli S, Catone S, Comini A, Michelini Z, Maggiorella MT, Sernicola L, Crostarosa F, Belli R, Mancini MG, Farcomeni S, Fagrouch Z, Ciccozzi M, Boros S, Liljestrom P, Norley S, Heeney J, Titti FProtective efficacy of a multicomponent vector vaccine in cynomolgus monkeys after intrarectal simian immunodeficiency virus challenge. J. Gen. Virol. 2004;85(Pt 5):1191-201

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

We investigated the protective efficacy of a systemic triple vector (DNA/rSFV/rMVA)-based vaccine against mucosal challenge with pathogenic simian immunodeficiency virus (SIV) in cynomolgus monkeys. Animals were immunized at week 0 with DNA (intradermally), at weeks 8 and 16 with recombinant Semliki Forest virus (rSFV, subcutaneously) and finally, at week 24, with recombinant modified vaccinia virus Ankara strain (rMVA, intramuscularly). Both DNA and recombinant viral vectors expressed a wide range of SIV proteins (Gag, Pol, Tat, Rev, Env and Nef). This immunization strategy elicited cell-mediated rather than humoral responses that were especially increased following the last boost. Upon intrarectal challenge with pathogenic SIVmac251, three of the four vaccinated monkeys dramatically abrogated virus load to undetectable levels up to 41 weeks after challenge. A major contribution to this vaccine effect appeared to be the T-cell-mediated immune response to vaccine antigens (Gag, Rev, Tat, Nef) seen in the early phase of infection in three of the four vaccinated monkeys. Indeed, the frequency of T-cells producing antigen-induced IFN-gamma mirrored virus clearance in the vaccinated and protected monkeys. These results, reminiscent of the efficacy of live attenuated virus vaccines, suggest that vaccination with a combination of many viral antigens can induce a robust and stable vaccine-induced immunity able to abrogate virus replication.

Haigwood NL, Montefiori DC, Sutton WF, McClure J, Watson AJ, Voss G, Hirsch VM, Richardson BA, Letvin NL, Hu SL, Johnson PRPassive immunotherapy in simian immunodeficiency virus-infected macaques accelerates the development of neutralizing antibodies. J. Virol. 2004;78(11):5983-95

Abstract & Topics (Click to display abstract, topics and IAVI Projects)     FREE PMC ARTICLE

Passively transferred neutralizing antibodies can block lentivirus infection, but their role in postexposure prophylaxis is poorly understood. In this nonhuman-primate study, the effects of short-term antibody therapy on 5-year disease progression, virus load, and host immunity were explored. We reported previously that postinfection passive treatment with polyclonal immune globulin with high neutralizing titers against SIVsmE660 (SIVIG) significantly improved the 67-week health of SIVsmE660-infected Macaca mulatta macaques. Four of six treated macaques maintained low or undetectable levels of virus in plasma, compared with one of ten controls, while two rapid progressors controlled viremia only as long as the SIVIG was present. SIVIG treatment delayed the de novo production of envelope (Env)-specific antibodies by 8 weeks (13). We show here that differences in disease progression were also significant at 5 years postinfection, excluding rapid progressors (P = 0.05). Macaques that maintained

Bower JF, Yang X, Sodroski J, Ross TMElicitation of neutralizing antibodies with DNA vaccines expressing soluble stabilized human immunodeficiency virus type 1 envelope glycoprotein trimers conjugated to C3d. J. Virol. 2004;78(9):4710-9

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

DNA vaccines expressing the envelope (Env) of human immunodeficiency virus type 1 (HIV-1) have been relatively ineffective at generating high-titer, long-lasting immune responses. Oligomeric or trimeric (gp140) forms of Env that more closely mimic the native proteins on the virion are often more effective immunogens than monomeric (gp120) envelopes. In this study, several forms of Env constructed from the HIV-1 isolate YU-2 (HIV-1(YU-2)) were tested for their immunogenic potential: a trimeric form of uncleaved (-) Env stabilized with a synthetic trimer motif isolated from the fibritin (FT) protein of the T4 bacteriophage, sgp140(YU-2)(-/FT), was compared to sgp140(YU-2)(-) without a synthetic trimerization domain, as well as to monomeric gp120(YU-2). DNA plasmids were constructed to express Env alone or fused to various copies of murine C3d (mC3d). BALB/c mice were vaccinated (day 1 and week 4) with DNA expressing a codon-optimized envelope gene insert, alone or fused to mC3d. Mice were subsequently boosted (week 8) with the DNA or recombinant Env protein. All mice had high anti-Env antibody titers regardless of the use of mC3d. Sera from mice vaccinated with DNA expressing non-C3d-fused trimers elicited neutralizing antibodies against homologous HIV-1(YU-2) virus infection in vitro. In contrast, sera from mice inoculated with DNA expressing Env-C3d protein trimers elicited antibody that neutralized both homologous HIV-1(YU-2) and heterologous HIV-1(ADA), albeit at low titers. Therefore, DNA vaccines expressing trimeric envelopes coupled to mC3d, expressed in vivo from codon-optimized sequences, elicit low titers of neutralizing antibodies against primary isolates of HIV-1.

Song B, Cayabyab M, Phan N, Wang L, Axthelm MK, Letvin NL, Sodroski JGNeutralization sensitivity of a simian-human immunodeficiency virus (SHIV-HXBc2P 3.2N) isolated from an infected rhesus macaque with neurological disease. Virology 2004;322(1):168-81

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

Simian-human immunodeficiency virus (SHIV) chimerae, after in vivo passage in monkeys, can induce acquired immunodeficiency syndrome (AIDS)-like illness and death. A monkey infected with the molecularly cloned, pathogenic SHIV-HXBc2P 3.2 exhibited multifocal granulomatous pneumonia as well as progressive neurological impairment characterized by tremors and pelvic limb weakness. SHIV-HXBc2P 3.2N was isolated from brain tissue explants and characterized. Viruses with the envelope glycoproteins of SHIV-HXBc2P 3.2N exhibited increased sensitivity to soluble CD4 and several neutralizing antibodies compared with viruses with the parental SHIV-HXBc2P 3.2 envelope glycoproteins. By contrast, viruses with SHIV-HXBc2P 3.2 and SHIV-HXBc2P 3.2N envelope glycoproteins were neutralized equivalently by 2G12 and 2F5 antibodies, which are rarely elicited in HIV-1-infected humans. A constellation of changes involving both gp120 and gp41 envelope glycoproteins was responsible for the difference in susceptibility to neutralization by most antibodies. Surprisingly, the gain of an N-linked glycosylation site in the gp41 ectodomain contributed greatly to neutralization sensitivity. Thus, the environment of the central nervous system, particularly in the context of immunodeficiency, allows the evolution of immunodeficiency viruses with greater susceptibility to neutralization by antibodies.

Yuan W, Craig S, Si Z, Farzan M, Sodroski JCD4-induced T-20 binding to human immunodeficiency virus type 1 gp120 blocks interaction with the CXCR4 coreceptor. J. Virol. 2004;78(10):5448-57

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

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.

Owens CM, Song B, Perron MJ, Yang PC, Stremlau M, Sodroski JBinding and susceptibility to postentry restriction factors in monkey cells are specified by distinct regions of the human immunodeficiency virus type 1 capsid. J. Virol. 2004;78(10):5423-37

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

In cells of Old World and some New World monkeys, dominant factors restrict human immunodeficiency virus type 1 (HIV-1) infections after virus entry. The simian immunodeficiency virus SIV(mac) is less susceptible to these restrictions, a property that is determined largely by the viral capsid protein. For this study, we altered exposed amino acid residues on the surface of the HIV-1 capsid, changing them to the corresponding residues found on the SIV(mac) capsid. We identified two distinct pathways of escape from early, postentry restriction in monkey cells. One set of mutants that were altered near the base of the cyclophilin A-binding loop of the N-terminal capsid domain or in the interdomain linker exhibited a decreased ability to bind the restricting factor(s). Consistent with the location of this putative factor-binding site, cyclophilin A and the restricting factor(s) cooperated to achieve the postentry block. A second set of mutants that were altered in the ridge formed by helices 3 and 6 of the N-terminal capsid domain efficiently bound the restricting factor(s) but were resistant to the consequences of factor binding. These results imply that binding of the simian restricting factor(s) is not sufficient to mediate the postentry block to HIV-1 and that SIV(mac) capsids escape the block by decreases in both factor binding and susceptibility to the effects of the factor(s).

Reeves JD, Miamidian JL, Biscone MJ, Lee FH, Ahmad N, Pierson TC, Doms RWImpact of mutations in the coreceptor binding site on human immunodeficiency virus type 1 fusion, infection, and entry inhibitor sensitivity. J. Virol. 2004;78(10):5476-85

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

An increasingly large number of antiviral agents that prevent entry of human immunodeficiency virus (HIV) into cells are in preclinical and clinical development. The envelope (Env) protein of HIV is the major viral determinant that affects sensitivity to these compounds. To understand how changes in Env can impact entry inhibitor sensitivity, we introduced six mutations into the conserved coreceptor binding site of the R5 HIV-1 strain YU-2 and measured the effect of these changes on CD4 and coreceptor binding, membrane fusion levels and rates, virus infection, and sensitivity to the fusion inhibitors enfuvirtide (T-20) and T-1249, the CCR5 inhibitor TAK-779, and an antibody to CD4. The mutations had little effect on CD4 binding but reduced CCR5 binding to various extents. In general, reductions in coreceptor binding efficiency resulted in slower fusion kinetics and increased sensitivity to TAK-779 and enfuvirtide. In addition, low CCR5 binding usually reduced overall fusion and infection levels. However, one mutation adjacent to the bridging sheet beta21 strand, P438A, had little effect on fusion activity, fusion rate, infectivity, or sensitivity to enfuvirtide or T-1249 despite causing a marked reduction in CCR5 binding and a significant increase in TAK-779 sensitivity. Thus, our findings indicate that changes in the coreceptor binding site of Env can modulate its fusion activity, infectivity, and entry inhibitor sensitivity by multiple mechanisms and suggest that reductions in coreceptor binding do not always result in prolonged fusion kinetics and increased sensitivity to enfuvirtide.

Pilcher CD, Eron JJ, Galvin S, Gay C, Cohen MSAcute HIV revisited: new opportunities for treatment and prevention. J. Clin. Invest. 2004;113(7):937-45

Abstract & Topics (Click to display abstract, topics and IAVI Projects)    

Inability to recognize incident infection has traditionally limited both scientific and public health approaches to HIV disease. Recently, some laboratories have begun adding HIV nucleic acid amplification testing to HIV diagnostic testing algorithms so that acute (antibody-negative) HIV infections can be routinely detected within the first 1-3 weeks of exposure. In this review article, we will highlight critical opportunities for HIV treatment and prevention that are presented by these diagnostic strategies.

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