A pathogenic threshold of virus load defined in simian immunodeficiency virus- or simian-human immunodeficiency virus-infected macaques - PubMed (original) (raw)

Comparative Study

A pathogenic threshold of virus load defined in simian immunodeficiency virus- or simian-human immunodeficiency virus-infected macaques

P Ten Haaft et al. J Virol. 1998 Dec.

Abstract

To determine if a specific pathogenic threshold of plasma viral RNA could be defined irrespective of virus strain, RNA levels in the plasma of more than 50 infected rhesus macaques (Macaca mulatta) were measured. Animals were inoculated intravenously with either simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) strains of known pathogenic potential (SIV8980, SIVsmm-3, SIVmac32H/J5, SIVmac32H/1XC, reverse transcriptase-SHIV, SHIV89.6p) or with attenuated strains (SHIVW6.1D, SHIVsf13, SHIVhan-2, SIVmacDeltanef, SHIVsf33). In animals inoculated with nonpathogenic strains, shortly after the primary peak of viremia viral RNA levels declined and remained below 10(4) RNA equivalents/ml of plasma between 6 and 12 weeks postinoculation. Animals infected with documented pathogenic strains maintained viral RNA levels higher than 10(5) RNA equivalents/ml of plasma. In animals infected with strains with low virulence, a decline in plasma RNA levels was observed, but with notable individual variation. Our results demonstrate that the disease-causing potential was predicted and determined by a threshold plasma virus load which remained greater than 10(5) RNA equivalents/ml of plasma 6 to 12 weeks after inoculation. A threshold virus load value which remained below 10(4) RNA equivalents/ml of plasma was indicative of a nonpathogenic course of infection.

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Figures

FIG. 1

Plasma viral RNA levels of two RT-SHIV-infected macaques (panels A and B) as determined by QC RT-PCR (SIV gag) and bDNA signal amplification (HIV-1 pol). Levels for weeks 2 and 8 after the infection of animal A were determined by using bDNA with 1 ml of diluted plasma to enlarge the dynamic range of the assay. For all other bDNA determinations, 1 ml of undiluted plasma was used. At week 0, both animals were negative according to both assays, and animal B was negative at week 12 as determined by bDNA testing. However, the values of the lower detection limits of the respective assays are plotted at these time points for graphical purposes. In the QC RT-PCR assay, the following 5′ biotinylated primers were used: 5′-TGGATTAGCAGAAAGCCTGTTGG-3′ (SIVsmmH4 homology at bp 1180 to 1202) and 5′-CCTCCTCTGCCACTAGGTGGTGC-3′ (SIVsmmH4 homology at bp 1424 to 1446). Briefly, 200 μl of plasma to be analyzed was added to 600 μl of guanidine-isothiocyanate-based lysis solution containing 300 copies of internal standard RNA. The RNA was precipitated by propanol-2 and was reverse transcribed and amplified with rTth DNA polymerase (Perkin-Elmer, Nieuwerkerk a/d IJssel, The Netherlands). The amplification products were hybridized in six fivefold dilutions to a capture probe that was covalently bound to Nucleolink microwells (Nunc A/S, Roskilde, Denmark). The amplification products were detected by a streptavidin-horseradish peroxidase-mediated colorimetric reaction. The amplified internal standard was hybridized to the rearranged 26-bp capture probe in separate microwells. The number of RNA copies in the plasma sample was calculated from the optical density of the sample wells compared to that of the corresponding internal standard well.

FIG. 2

Plasma viral RNA levels of individual macaques (represented by various open and filled symbols) infected with various SIV or SHIV strains and mean viral RNA levels (represented by lines and open squares) as determined by QC RT-PCR. n, number of animals used in the study.

FIG. 3

Comparison of mean plasma viral RNA levels determined after infection with various SIV or SHIV strains. The shaded area represents levels of virus load in animals with infections which have pathogenic potential (i.e., the danger zone between the pathogenic and nonpathogenic threshold). One SHIV89.6p-infected animal died within the 12-week study period due to a non-AIDS-related disease. One SIV8980-infected animal as well as one SIVmac32H/1XC-infected animal developed AIDS and was euthanized within the 12-week study period.

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A pathogenic threshold of virus load defined in simian immunodeficiency virus- or simian-human immunodeficiency virus-infected macaques - PubMed (original) (raw)