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Using a Simian Immunodeficiency Virus (SIV) rhesus macaque model to study the biology of HIV-1 mucosal transmission, we demonstrated that although Toll-like receptor (TLR) agonists could induce type-1 interferon responses, it was not sufficient to prevent sexual transmission of SIV. In the animals treated with the TLR7 agonist, imiquimod, and the TLR9 agonist, CpG, we detected IFN-alpha and other anti-viral effecter molecules in vaginal-cervical secretions. However, both TLR agonists also induced proinflammatory cytokines expressions in the genital mucosa. In imiquimod treated animals, we showed a massive mononuclear cell infiltration consisting of activated CD4+ T cells, DC, and beta-chemokine-secreting cells. All the TLR agonist-treated monkeys became infected after intravaginal SIV challenge. Importantly, the set-point vRNA level in TLR ligand treated animals was significantly higher than that in control animals. We also studied the effectiveness of CpG when used as an adjuvant in combination with a therapeutic vaccine in SIV infected animals receiving antiretroviral therapy (ART). We found that compared to saline-treated control animals, the animals treated only with the therapeutic vaccine, AT2-inactivated SIV239, showed significantly lower plasma vRNA levels after ART stopped. However the CpG adjuvant treatment attenuated the protective effect of AT-2 inactivated SIV as a therapeutic AIDS vaccine, even though AT2-inactivated SIV239+CpG vaccinated animals showed augmented SIV specific IgG antibody responses as compared to all the other 3 groups. Animals treated with CpG alone showed significantly higher level of viral replication associated with increased SIV specific T cell activations. Our findings dramatically highlight the value of SIV/rhesus macaque models in studying HIV pathogenesis and evaluating the safety and efficacy of new immunological strategies to interfere with HIV infection.
For many years, experiments using chimpanzees have been instrumental in advancing scientific knowledge and have led to new medicines to prevent life-threatening and debilitating diseases. However, recent advances in alternate research tools have rendered chimpanzees largely unnecessary as research subjects. The Institute of Medicine, in collaboration with the National Research Council, conducted an in-depth analysis of the scientific necessity for chimpanzees in NIH-funded biomedical and behavioral research. The committee concludes that while the chimpanzee has been a valuable animal model in the past, most current biomedical research use of chimpanzees is not necessary, though noted that it is impossible to predict whether research on emerging or new diseases may necessitate chimpanzees in the future.
Efficacy assessment of AIDS vaccines relies both on pre-clinically challenging immunised monkeys with a pathogenic virus and subsequent monitoring of infection rates in large human trials. Conventional parameters of vaccine-induced immune responses do not completely predict outcome. Moreover, existing methods for testing cellular immunity are sophisticated and difficult to establish in resource-limited settings, thereby constraining large studies. There is a need for study models that bridge the gap between preclinical and clinical vaccine testing, and which are able to predict a virus-specific vaccine effect before actual challenge. Virus replication kinetics (VVR) on ConA-stimulated peripheral blood mononuclear cells (PBMC) was used as an ex vivo model to mimic the interaction between different components of the immune system and viral infection. PBMCs were obtained from the 17 experimental rhesus monkeys before immunisation and subsequently at 12, 26 and 44 weeks during immunisation (wdi). Before immunization, VVR of vaccine-naïve PBMCs varied between individual animals by between >430-fold and >60-fold after 7 and 10 days of infection cultures. VVR of sham-vaccinated control monkeys remained constant over 44 the weeks. However, VVR of immunised animals was significantly attenuated during this follow-up period. This effect was not influenced by the MHC- class 1 Mamu-A*01 allele, which is normally associated with slow disease progression. VVR was instead dependent on the number of IFNγ-producing cells (p=0.001), CD8+ T-cell non-cytotoxic antiviral response (CNAR) (p=0.01) and MIP-1α (p=0.013). High VVR correlated with increased CXCL10, IL-1β and MIP-1β. Importantly, pre-challenge VVR, CXCL10, IL-1β and MIP-1β but not IFNγ correlated directly with acute plasma viremia and inversely with memory CD4+ T-cell counts after SIVmac239 challenge. VVR was thus able to predict disease progression and the protective capacity of the vaccine regime. Likewise, pre-challenge CNAR, MIP-1α and IL-10 were associated inversely with acute-phase plasma viremia and directly with memory CD4+ T-cell concentrations in blood. When applied to human studies, this ex vivo infection technique could predict the efficacy of candidate AIDS vaccines prior to phase III clinical trials.
Understanding the host response immediately following mucosal HIV-1 infection will be pivotal in determining whether the immune response induced by a vaccine will successfully sense and control viral replication. In order for effective vaccine strategies and modalities to be developed, these earliest immunological events must be fully assessed in a non-biased manner. Nonhuman primates (NHP), specifically Rhesus macaques (RM), serve as a model to investigate the immunological landscape immediately post-challenge and to define the spatiotemporal path of simian immunodeficiency virus (SIV). SIV infection of RM serves as a model of human HIV infection as it recapitulates many of the virological, immunological, and pathological features of HIV infection vii in the human host. In this thesis I will test the hypothesis whether transcriptional analysis will allow a sensitive measure of the early innate immune responses that accompany detection of the SIV virus in the periphery. I have determined that an early inflammatory profile arises early in tissues proximal to the challenge site that precedes widespread immune activation and the systemic antiviral interferon response. This study defines in detail the spatiotemporal relationship between virus and host immune response and may be a valuable resource in guiding future vaccine design strategies.
The first book to specifically cover the molecular biology of retroviruses - of immense importance since the high profile of HIV. International contributors provide detailed reviews of the latest knowledge. An excellent text for both medical and non-medical researchers, it also serves as an illuminating introduction for scientists active in other areas.
This volume summarizes recent advances in understanding the mechanisms of HIV-1 latency, in characterizing residual viral reservoirs, and in developing targeted interventions to reduce HIV-1 persistence during antiretroviral therapy. Specific chapters address the molecular mechanisms that govern and regulate HIV-1 transcription and latency; assays and technical approaches to quantify viral reservoirs in humans and animal models; the complex interchange between viral reservoirs and the host immune system; computational strategies to model viral reservoir dynamics; and the development of therapeutic approaches that target viral reservoir cells. With contributions from an interdisciplinary group of investigators that cover a broad spectrum of subjects, from molecular virology to proof-of-principle clinical trials, this book is a valuable resource for basic scientists, translational investigators, infectious-disease physicians, individuals living with HIV/AIDS and the general public.