Characterization of primary isolate-like variants of simian-human immunodeficiency virus - PubMed (original) (raw)

. 1999 Dec;73(12):10199-207.

doi: 10.1128/JVI.73.12.10199-10207.1999.

P L Earl, B Moss, K A Reimann, M S Wyand, K H Manson, M Bilska, J T Zhou, C D Pauza, P W Parren, D R Burton, J G Sodroski, N L Letvin, D C Montefiori

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Characterization of primary isolate-like variants of simian-human immunodeficiency virus

J M Crawford et al. J Virol. 1999 Dec.

Abstract

Several different strains of simian-human immunodeficiency virus (SHIV) that contain the envelope glycoproteins of either T-cell-line-adapted (TCLA) strains or primary isolates of human immunodeficiency virus type 1 (HIV-1) are now available. One of the advantages of these chimeric viruses is their application to studies of HIV-1-specific neutralizing antibodies in preclinical AIDS vaccine studies in nonhuman primates. In this regard, an important consideration is the spectrum of antigenic properties exhibited by the different envelope glycoproteins used for SHIV construction. The antigenic properties of six SHIV variants were characterized here in neutralization assays with recombinant soluble CD4 (rsCD4), monoclonal antibodies, and serum samples from SHIV-infected macaques and HIV-1-infected individuals. Neutralization of SHIV variants HXBc2, KU2, 89.6, and 89.6P by autologous and heterologous sera from SHIV-infected macaques was restricted to an extent that these viruses may be considered heterologous to one another in their major neutralization determinants. Little or no variation was seen in the neutralization determinants on SHIV variants 89.6P, 89.6PD, and SHIV-KB9. Neutralization of SHIV HXBc2 by sera from HXBc2-infected macaques could be blocked with autologous V3-loop peptide; this was less true in the case of SHIV 89.6 and sera from SHIV 89.6-infected macaques. The poorly immunogenic but highly conserved epitope for monoclonal antibody IgG1b12 was a target for neutralization on SHIV variants HXBc2, KU2, and 89.6 but not on 89.6P and KB9. The 2G12 epitope was a target for neutralization on all five SHIV variants. SHIV variants KU2, 89.6, 89.6P, 89.6PD, and KB9 exhibited antigenic properties characteristic of primary isolates by being relatively insensitive to neutralization in peripheral blood mononuclear cells with serum samples from HIV-1-infected individuals and 12-fold to 38-fold less sensitive to inhibition with recombinant soluble CD4 than TCLA strains of HIV-1. The utility of nonhuman primate models in AIDS vaccine development is strengthened by the availability of SHIV variants that are heterologous in their neutralization determinants and exhibit antigenic properties shared with primary isolates.

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Figures

FIG. 1

FIG. 1

Inhibition of HIV-1 and SHIV infection with rsCD4. Viruses were incubated with various concentrations of rsCD4 ranging from 0.002 to 5 μg/ml and then examined for infectivity in MT-2 cells as described for antibody-mediated neutralization in Materials and Methods. The height of each bar corresponds to the dose of rsCD4 that was required to provide 50% protection from virus-induced cell killing.

FIG. 2

FIG. 2

Ability of V3-loop peptides to absorb neutralizing antibodies in serum samples from SHIV-infected macaques. Serum samples from macaques infected with either SHIV variant HXBc2 or 89.6 were incubated in the presence and absence of V3-loop peptides (50 μg/ml) and then examined for neutralizing antibody titer to the corresponding homologous SHIV in MT-2 cells as described in Materials and Methods. The height of each bar corresponds to the reciprocal serum dilution at which 50% of cells were protected from virus-induced killing effects. Values above each bar are the percent reductions in neutralization titer relative to that of the corresponding serum sample that was incubated with an equal volume of growth medium (GM) in place of V3-loop peptide. Serum samples from animals 18001, 18024, and 18062 were obtained after 27 weeks of infection with HXBc2. Serum samples from animals 123-93 and 504-92 were obtained after 124 weeks of infection, and serum samples 259-94 and 305-94 were obtained after 16 weeks of infection with 89.6.

FIG. 3

FIG. 3

V3-loop reactivity measured by peptide ELISA with serum samples from SHIV-infected macaques. Serum samples were assessed at a 1:50 dilution for antibodies reactive with IIIB and 89.6 V3-loop peptides in an ELISA as described in Materials and Methods. Serum samples are the same as those described in the legend to Fig. 2. A negative control serum sample was obtained from a healthy, noninfected rhesus macaque. O.D., optical density.

FIG. 4

FIG. 4

Neutralization of SHIV variants 89.6 and 89.6P by IgG1b12 in rhesus PBMC. Virus stocks were grown in human PBMC and assayed in rhesus macaque PBMC. Virus (500 TCID50) was incubated for 1 h at 37°C with various concentrations of IgG1b12 in 96-well U-bottom plates. Rhesus PBMC (stimulated with phytohemagglutinin-P) in IL-2 growth medium were added (500,000 cells/well), and the plates were incubated overnight. The medium was changed completely twice to remove the virus inoculum. Viral p27 was quantified at a time when virus production in the absence of IgG1b12 was in a linear phase of increase and had yet to peak (2,133 ± 438 pg/ml for SHIV variant 89.6 and 2,319 ± 571 pg/ml for SHIV variant 89.6P). Error bars are used to show the standard deviation for average p27 values in triplicate wells. Values below the data points on the 89.6 curve represent percent reductions in p27 synthesis relative to infection in the absence of IgG1b12.

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