Biologic and genetic characterization of a panel of 60 human immunodeficiency virus type 1 isolates, representing clades A, B, C, D, CRF01_AE, and CRF02_AG, for the development and assessment of candidate vaccines - PubMed (original) (raw)
Comparative Study
Biologic and genetic characterization of a panel of 60 human immunodeficiency virus type 1 isolates, representing clades A, B, C, D, CRF01_AE, and CRF02_AG, for the development and assessment of candidate vaccines
Bruce K Brown et al. J Virol. 2005 May.
Abstract
A critical priority for human immunodeficiency virus type 1 (HIV-1) vaccine development is standardization of reagents and assays for evaluation of immune responses elicited by candidate vaccines. To provide a panel of viral reagents from multiple vaccine trial sites, 60 international HIV-1 isolates were expanded in peripheral blood mononuclear cells and characterized both genetically and biologically. Ten isolates each from clades A, B, C, and D and 10 isolates each from CRF01_AE and CRF02_AG were prepared from individuals whose HIV-1 infection was evaluated by complete genome sequencing. The main criterion for selection was that the candidate isolate was pure clade or pure circulating recombinant. After expansion in culture, the complete envelope (gp160) of each isolate was verified by sequencing. The 50% tissue culture infectious dose and p24 antigen concentration for each viral stock were determined; no correlation between these two biologic parameters was found. Syncytium formation in MT-2 cells and CCR5 or CXCR4 coreceptor usage were determined for all isolates. Isolates were also screened for neutralization by soluble CD4, a cocktail of monoclonal antibodies, and a pool of HIV-1-positive patient sera. The panel consists of 49 nonsyncytium-inducing isolates that use CCR5 as a major coreceptor and 11 syncytium-inducing isolates that use only CXCR4 or both coreceptors. Neutralization profiles suggest that the panel contains both neutralization-sensitive and -resistant isolates. This collection of HIV-1 isolates represents the six major globally prevalent strains, is exceptionally large and well characterized, and provides an important resource for standardization of immunogenicity assessment in HIV-1 vaccine trials.
Figures
FIG. 1.
Global map of U.S. government-funded HIV-1 vaccine development sites for the DOD, Centers for Disease Control and Prevention, and HVTN.
FIG. 2.
Genetic and biological characterization of 60 international HIV-1 isolates. The 60 viruses were either expanded from previously established stocks or newly isolated. Clade purity was assessed either by performing FL sequencing or by comparing the envelope gene to previously obtained FL sequences from primary PBMC. GenBank accession numbers are listed for each FL and envelope sequence. The p24 concentration, titer, syncytial phenotype, coreceptor usage, and neutralization profile are indicated for each isolate. For the neutralization profiles, blue indicates ≤50% neutralization, while red indicates >50% neutralization. a, GenBank accession numbers from previously published sources are in black, and numbers submitted for this communication are in red. b, TCID50 was measured from 25 μl of virus stock (see Materials and Methods). NA, not applicable, as the isolate env sequence is contained within the new FL sequence, obtained from culture of the virus stock. Shaded rows indicate isolates that are being used for current or candidate viruses.
FIG.3.
Phylogenetic relationships of HIV-1 sequences from the international panel. (A) FL sequences were previously generated for 39 of the virus isolates, and 21 were newly sequenced for this study. Preexisting (plain text) and newly obtained (boldface) sequences were aligned with reference sequences (italics) of HIV-1 subtypes and relevant CRF. Strain KER2018 is hypermutated. (B) After expansion of the 60 viruses in primary PBMC coculture, gp160 was amplified from the cellular DNA and sequenced. The new sequences (boldface) were aligned with reference sequences (italics) of HIV-1 subtypes and relevant CRF. Each alignment was gap stripped, resampled using SEQBOOT (100 iterations), and analyzed with DNADIST, NEIGHBOR, and CONSENSE. Representative trees are shown with bootstrap values recorded for important nodes. The scale represents a 10% difference.
FIG. 4.
Characterization of gp160 sequences. (A) Diversity of envelope sequences within subtypes and CRF represented by distributions of pair-wise protein distances. (B) Parameters implicated in neutralization resistance include average number of potential N-glycosylation sites (N-gly, top) and length of hypervariable loops (V4, bottom). Large squares indicate the means, while small squares represent the mean ± 1 standard deviation. Subtypes are arranged in order of increasing glycosylation or loop length.
FIG. 5.
HIV-1 TCID50 and p24 concentrations are not correlated. The calculated TCID50 was compared to viral stock p24 concentration by linear regression analysis. The trend line shows that the TCID50 and p24 concentrations have no correlation (_r_2 = 0.147).
FIG. 6.
Characterization of syncytium induction and coreceptor usage. (A) Viral isolate clade was compared to syncytium induction (right-hand bars) as measured by the MT-2 assay and coreceptor usage (left-hand bars) as measured by the GHOST assay (see Materials and Methods). (B) Five isolates were further characterized by performing competition assays using AMD3100 (AMD) and RANTES to determine if the isolates utilized both CCR5 and CXCR4 coreceptors.
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