Variability of Bio-Clinical Parameters in Chinese-Origin Rhesus Macaques Infected with Simian Immunodeficiency Virus: A Nonhuman Primate AIDS Model

Abstract

BackgroundAlthough 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 FindingsBy 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 (ir) SIVmac239, intravenous (iv) SIVmac239, or iv 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 (ir or iv)-infected than in SIVmac251 (iv)-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 (ir or iv)-infected than in SIVmac251 (iv)-infected animals. No significant difference in bio-clinical endpoints was observed in animals challenged with ir or iv SIVmac239. The variability (standard deviation) in peak/set-point VL was nearly one-half lower in animals infected with SIVmac239 (ir or iv) than in those infected with SIVmac251 (iv), allowing that the same treatment-related difference can be detected with one-half fewer animals using SIVmac239 than using SIVmac251.Conclusion/SignificanceThese 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.

Plasmodium infection reduces the volume of the viral reservoir in SIV-infected rhesus macaques receiving antiretroviral therapy

“…Twelve Chinese-origin rhesus macaques (Macaca mulatta) were inoculated intravenously with 10,000 50% tissue culture infectious doses of SIVmac251 and were randomly divided into two groups (n = 6 per group): the ART group (ART only) and the ART + Pc group (ART plus Pc infection). SIV infection resulted in certain typical virological and immunological changes in the monkeys that were similar to those reported previously (Additional file 1: Figure S1) [15]. The animals in the ART + Pc group displayed typical clinical manifestations of malaria during Pc infection (data not shown).…”

Induction of CD8+ Regulatory T Cells Protects Macaques against SIV Challenge

“…To that end, we (B-F) Anti-SIV activity of CD8 + T cells after 60 days following oral immunization in a delayed (B), insert (C), or allogenic (D) culture system, in the presence of MHC-Ia/ABC or MHC-Ib/E antibodies (E), and in CD8 + T cells depleted of TCRgd + or Vb8 + subset (F). See also Figure S2 and Table S2. challenged the eight iSIV/LP-immunized and eight control animals intrarectally with a high dose (100,000 TCID 50 ) of SIVmac239 3 months after immunization (Chen et al, 2011). Surprisingly, the eight immunized animals were fully protected without any detectable level of plasma SIV RNA or PBMC proviral DNA.…”

“…Marx; Chen et al, 2011). The culture supernatants were collected at peak virus production and inactivated first with 250 mM AT-2 (Sigma-Aldrich, St. Louis) (Rossio et al, 1998) and then by heating at 56 C for 30 min.…”

“…To test this hypothesis, we used the model of the simian immunodeficiency virus (SIV) in macaques of Chinese origin, which best mimics HIV-1 infection in humans (Chen et al, 2011;Ling et al, 2002;Marcondes et al, 2006;Stahl-Hennig et al, 2007). We assessed whether an oral vaccine that favors immune tolerance and consists of Lactobacillus plantarum (LP) (Kleerebezem et al, 2003), a digestive tract commensal bacterium (Grangette et al, 2005;van Baarlen et al, 2009), and inactivated SIV would induce CD4 + T cell unresponsiveness/tolerance toward SIV antigens, which would in turn inhibit viral replication in vivo.…”

A 30-year journey of trial and error towards a tolerogenic AIDS vaccine

“…As a consequence of this absence of digestive immune reactivity, the 17 Indian RMs vaccinated with iSIV + LP and challenged intrarectally, not surprisingly, were infected. The absence of immunoreactivity of Indian RMs toward the ingested vaccine (iSIV particles) could have resulted from the destruction or the damage of these particles before or after their intragastric administration; a difference in the genetic background of the two RM subspecies could also be envisaged [22, 23]. …”