Variability of bio-clinical parameters in Chinese-origin Rhesus macaques infected with simian immunodeficiency virus: a nonhuman primate AIDS model

Abstract

Background: Although Chinese-origin Rhesus macaques (Ch RhMs) infected with simian immunodeficiency virus (SIV) have been used for many years to evaluate the efficacy of AIDS vaccines and therapeutics, the bio-clinical variability of such a nonhuman primate AIDS model was so far not established.

Methodology/principal findings: By randomizing 150 (78 male and 72 female) Ch RhMs with diverse MHC class I alleles into 3 groups (50 animals per group) challenged with intrarectal (i.r.) SIVmac239, intravenous (i.v.) SIVmac239, or i.v. SIVmac251, we evaluated variability in bio-clinical endpoints for 118 weeks. All SIV-challenged Ch RhMs became seropositive for SIV during 1-2 weeks. Plasma viral load (VL) peaked at weeks 1-2 and then declined to set-point levels as from week 5. The set-point VL was 30 fold higher in SIVmac239 (i.r. or i.v.)-infected than in SIVmac251 (i.v.)-infected animals. This difference in plasma VL increased overtime (>100 fold as from week 68). The rates of progression to AIDS or death were more rapid in SIVmac239 (i.r. or i.v.)-infected than in SIVmac251 (i.v.)-infected animals. No significant difference in bio-clinical endpoints was observed in animals challenged with i.r. or i.v. SIVmac239. The variability (standard deviation) in peak/set-point VL was nearly one-half lower in animals infected with SIVmac239 (i.r. or i.v.) than in those infected with SIVmac251 (i.v.), allowing that the same treatment-related difference can be detected with one-half fewer animals using SIVmac239 than using SIVmac251.

Conclusion/significance: These results provide solid estimates of variability in bio-clinical endpoints needed when designing studies using the Ch RhM SIV model and contribute to the improving quality and standardization of preclinical studies.

Figure 1. Distribution of MHC class I alleles (including patterns of shared alleles) by the sequence-specific primers (SSP)-PCR assay in the whole 150 Ch RhMs (A), 50 ir SIVmac239-infected Ch RhMs (B), 50 iv SIVmac239-infected Ch RhMs (C), or 50 iv SIVmac251-infected Ch RhMs (D).

Note that the 3 out of 150 (2%) samples were negative for the SSP-PCR assay.

Figure 2. Humoral immune responses in Ch RhMs randomly challenged with pathogenic SIVmac239 (ir or iv) or SIVmac251 (iv).

(A) Anti-SIV IgM antibody titers (mean ± SD) in plasma following 118 weeks post viral challenge. (B) Anti-SIV IgA antibody titers (mean ± SD) in plasma following 118 weeks post viral challenge. (C) Anti-SIV IgG antibody titers (mean ± SD) in plasma following 118 weeks post viral challenge.

Figure 3. CD4+ T-cell counts and animal survivals in Ch RhMs randomly challenged with pathogenic SIVmac239 (ir or iv) or SIVmac251 (iv).

(A) Evolution of CD4⁺ T-cell counts (mean ± SD) following 118 weeks post viral challenge. (B) Kaplan-Meier plot of probability for maintaining a stable CD4⁺ T-cell count following 118 weeks post viral challenge. (C) Kaplan-Meier plot of survival probability of Ch RhMs following 118 weeks post viral challenge. (D) Survival curve of SIVmac239-infected Ch RhMs with or without MHC-I B01 allele.

Figure 4. Plasma SIV RNA viral loads in Ch RhMs randomly challenged with pathogenic SIVmac239 (ir or iv) or SIVmac251 (iv).

(A) Evolution of plasma SIV RNA viral loads (geometric mean ± SE) following 118 weeks post viral challenge. (B) Smoothed curve of the SIV RNA levels in plasma of animals following 52 weeks post viral challenge with SIVmac239 (ir or iv) or SIVmac251 (iv). (C) Smoothed curve of the SIV RNA levels in plasma of SIVmac239-infected Ch RhMs with or without MHC-I B17 allele.