Chimpanzees in Biomedical and Behavioral Research Assessing the Necessity (2011) / Chapter Skim
Currently Skimming:
Appendix B: Commissioned Paper: Comparison of Immunity to Pathogens in Humans, Chimpanzees, and Macaques
Appendix B: Commissioned Paper: Comparison of Immunity to Pathogens in Humans, Chimpanzees, and Macaques
Pages 91-166
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 91... ...
Professor of Microbiology and Immunology Director Oregon National Primate Research Center Christopher M Walker, Ph.D.
|
From page 92... ...
Because the outcome of infection is governed by carefully coordinated innate and adaptive immune responses, and pathogens have evolved strategies to evade these defenses, use of animal models that recapitulate key features of human infection is critical. Successful nonhuman primate models closely emulate human immunity, inflammation, and disease sequelae.
|
From page 93... ...
Contemporary examples of primate infectious disease models that replicate most if not all features of human infection and immunity are provided. Where infection models are not perfectly matched in humans and nonhuman primates, differences have provided insight into key features of the relationship between the pathogen and its human host.
|
From page 94... ...
Here, factors that determine the suitability of chimpanzees for research on infectious diseases are reviewed. Malaria, respiratory syncytial virus (RSV)
|
From page 95... ...
. Recent studies have also included sophisticated analyses of humoral and cellular immune responses with goal of identifying protective correlates in human volunteers (Good, 2011)
|
From page 96... ...
Other available nonhuman primates have higher body temperatures and so chimpanzees are uniquely suited for pre-clinical evaluation of temperature-sensitive vaccine candidates, which comprise all of the candidates evaluated in clinical trials to date. In addition, the chimpanzee experiments added to a body of evidence that both live attenuated vaccines and vectored vaccines are not associated with enhanced disease.
|
From page 97... ...
This discovery brought pause to the vaccine field, since none of the vaccines in testing could elicit neutralizing antibodies against the primary isolates that required CCR5 for infection. Later attempts to block infection using a human monoclonal against a primary HIV-1 challenge were also less successful, though they showed some effect in reducing acute phase viremia (Conley et al., 1996)
|
From page 98... ...
It is now apparent that HIV originated from a chimpanzee simian immunodeficiency virus (SIVcpz) introduced into human populations by zoonotic infection at least three times since the beginning of the 20th century (Keele et al., 2009a)
|
From page 99... ...
Use of chimpanzees in hepatitis research predated the discovery of the viruses that caused type A and B hepatitis. Sporadic outbreaks of liver disease in chimpanzee colonies with occasional zoonotic transmission indicated that the animals might be susceptible to infection with human viruses (Maynard et al., 1972a)
|
From page 100... ...
Enteric Hepatitis Viruses HAV and HEV cause acute hepatitis and self-limited infection in humans and chimpanzees. Although liver disease may be somewhat milder in chimpanzees, the kinetics and magnitude of virus replication, onset of liver disease, and histopathological changes in the liver are similar to those in HAV-infected humans (Dienstag et al., 1975, 1976)
|
From page 101... ...
This situation has highlighted a gap in knowledge about mechanisms of immunity and hepatocellular injury caused by HAV. Very recent studies in chimpanzees provided insight into patterns of innate immunity and host gene expression immediately after infection with HAV and HEV, with the goal of understanding the pathogenesis of these infections and how they compare to responses elicited by HCV that often establishes a persistent infection (Lanford et al., 2011; Yu et al., 2010a)
|
From page 102... ...
. As discussed below, new and perhaps more effective approaches to reverse immune tolerance are being considered for chronic viral hepatitis.
|
From page 103... ...
. Liver disease is typically mild in persistently infected chimpanzees, as it is in most humans with chronic hepatitis C
|
From page 104... ...
More basic studies focused on the balance between innate and adaptive immunity in HCV infection outcome (Barth et al., 2011) , and patterns of host gene expression in liver before infection is clinically evident in humans (Yu et al., 2010b)
|
From page 105... ...
As noted above, liver disease caused by chronic hepatitis B and C is usually at the mild end of the spectrum observed in humans, but to date this has not been a barrier to successful de velopment of vaccines or therapeutics that target the viruses. Comparative and Evolutionary Immunology in Humans and Chimpanzees Humans and chimpanzees diverged approximately 5-7 million years ago.
|
From page 106... ...
. Humans and chimpanzees have orthologous MHC class I A, B, and C loci.
|
From page 107... ...
KIR gene diversity between the species may influence the outcome of chimpanzee infections with human pathogens. Resolution of human HCV infections has been associated with homozygous expression of the KIR2DL3 receptor and its specific HLA-C ligand (Khakoo et al., 2004)
|
From page 108... ...
that recognizes antigens presented by MHC class I or II complexes. TcRβ chain diversity is generated by the rearrangement of V, D, J, and C regions.
|
From page 109... ...
. These studies have provided insight into natural selection of human and chimpanzee defense genes by infectious diseases.
|
From page 110... ...
Most importantly, some of these molecules (and others not associated with immunity) are considered targets for monoclonal antibody therapy of human diseases.
|
From page 111... ...
Virus-specific T cell responses in chimpanzees can be very precisely quantified by functional assays that measure production of effector cytokines or killing. As noted above, evolutionary studies of the chimpanzee Patr complex provided insight into MHC class I and II restriction of the T cell response to hepatitis viruses in chimpanzees.
|
From page 112... ...
The first goal is to facilitate development of vaccines that skew the outcome of HCV infection from persistence to resolution. The second goal is to determine the defect that underlies CD4+ and CD8+ T cell failure in chronic hepatitis C (and B)
|
From page 113... ...
Indeed, the T cell depletion studies in chimpanzees led directly to the design of a recombinant adenovirus vector that expressed the nonstructural proteins of HCV that are predominantly targeted by the cellular immune response (Folgori et al., 2006)
|
From page 114... ...
. Blockade of multiple pathways is feasible, but the approach carries risk as these pathways were designed to temper unwanted or dangerous immune responses (Callendret and Walker, 2011)
|
From page 115... ...
New technologies offer great promise in unraveling molecular mechanisms underlying the failure of immunity in acute and persistent infections with viruses like HAV, HBV, and HCV. It is now possible to probe the innate and adaptive immune responses, and how they are coordinated, a level of resolution not possible a few short years ago.
|
From page 116... ...
Macaques share many similarities with humans and chimpanzees in their hematology, reproductive biology, neurological development, behavior, immunogenetics, and immune responses to pathogens. Much of this subsequent research has focused on models in the rhesus macaque, due to their relative ease of breeding in captivity and high adaptability to novel environments.
|
From page 117... ...
To introduce this subject, we provide a brief review of host restriction factors and infectious disease models for human disease in the macaque. Host Factors in Macaque Models for Human Diseases Host Interactions with Pathogens at the Cellular Level A major distinction for macaques compared with chimpanzees is that their greater genetic distance from humans results in lack of susceptibility to certain human pathogens.
|
From page 118... ...
. A well-adapted virus is one that can peacefully coexist with the host in the absence of pathogenic effects, an example being SIV in African nonhuman primates (sooty mangabeys, African green monkeys, and mandrills)
|
From page 119... ...
. In addition, experiments using these agents require special containment to reduce biohazardous exposure to humans and other nonhuman primates.
|
From page 120... ...
Furthermore, many of the findings could not be directly tested in humans for ethical or safety reasons. TABLE 1 Examples of Lessons Learned from Macaque Models for Human Diseases Human Macaque Pathogen Pathogen Concept Revealed References HIV-1 SIV Mucosal routes of infection require (Hirsch and Lifson, greater doses than parenteral for 2000; Sodora et al., productive infection after a single 1997)
|
From page 121... ...
Prior work had focused on specific regions of the genome that encode gene members of the immune system, as noted below. Major Histocompatibility Complex MHC loci in rhesus macaques have been explored and compared, with a great deal of progress in the rhesus macaque.
|
From page 122... ...
The KIR Gene Family As noted above in the section on chimpanzees, MHC class I molecules are ligands for the KIRs, which are expressed by natural killer cells and T cells. As with chimpanzee KIRs, the interactions between these molecules contribute to both innate and adaptive immunity, and combinations of MHC class I and KIR variants influence resistance to infections, susceptibility to autoimmune diseases and complications of pregnancy, and outcomes of transplantation (Parham, 2005)
|
From page 123... ...
and the soluble forms, or antibodies, that result, is generated by somatic recombination as with the TCR. The immunoglobulin loci for antibodies are similarly arranged in the rhesus macaque as in humans, and the antibodies have the same structures, with clear homologs identified for IgG and IgA classes and for subclasses of IgG (Scinicariello et al., 2004)
|
From page 124... ...
. The relative contribution of specific types of cells in innate and adaptive immune responses in the outbred Macaca species has been made possible by infusion studies using murine monoclonals directed at human CD8, CD4, CD16, CD20 (or other cell surface markers of interest)
|
From page 125... ...
in response to SIV or SHIV infection is similar to that of HIV-1 in humans. In acute SIV infection, CD8+ T cells were shown to be very important for viral control (Schmitz et al., 1999)
|
From page 126... ...
. There is now extensive molecular and sequence data of both viral variants and antibodies that HIV and SIV infection leads to similar B cell responses in humans and macaques, respectively.
|
From page 127... ...
These viral vectors are attractive because they stimulate innate and adaptive immunity and persist long enough to provide a strong antigen pool to boost B cells, much as the currently licensed live attenuated vaccines. The ability to challenge in macaques prior to testing in humans provides a measure of confidence that the immune responses elicited by
|
From page 128... ...
They can be delivered multiple times without inducing anti-vector immunity that limits the effectiveness of viral vectors. Another noteworthy area of active research in nonhuman primate models is the development of protein immunogens and improved adjuvants.
|
From page 129... ...
These studies have provided key observations about the immune responses elicited and how these have correlated with protection from infection. A critical example of this is the T cell-focused vaccines based on a non-replicating recombinant human adenovirus (Ad5)
|
From page 130... ...
To move this approach into the clinic, it will require making HIV antigens in an attenuated hCMV vector, since hCMV is a high-risk infection for fetuses and immunecompromised humans. Immunity to adapted viruses may provide clues for non-adapted infection Because both HIV-1 and HIV-2 are derived from naturally occurring SIVs, understanding the immune responses in the host to which they are adapted could yield clues as to whether immunity in the non-adapted host contributes to pathogenesis (Silvestri, 2009)
|
From page 131... ...
Gene therapy as proof of principle for antibody-mediated protection One of the most innovative uses of the SIV/macaque model was to directly prove that neutralizing antibodies expressed in vivo could prevent infection. This question was critically important to address because work prior to this point had suggested that only extraordinarily high levels of antibodies would be effective in preventing infection.
|
From page 132... ...
. Further studies on SIV and TB co-infection indicate that events during acute HIV infection are likely to include distortions in proinflammatory and anti-inflammatory T cell responses within the granuloma that have significant effects on reactivation of latent TB.
|
From page 133... ...
. To test for improved vaccines, there is currently a model for yellow fever using the YFV-Dakar strain of virus that has previously been characterized as viscerotropic and capable of being lethal in rhesus macaques (Monath et al., 1981)
|
From page 134... ...
. CONCLUSIONS AND FUTURE USES OF NONHUMAN PRIMATE MODELS, INCLUDING THE CHIMPANZEE • Chimpanzees have been essential for the study of human patho gens that do not infect lower species or reproduce key features of human disease.
|
From page 135... ...
These tissues are often not available from humans because biop sies are not medically indicated. Also, critical aspects of innate and adaptive immune responses may be missed in humans be cause early stages of the infection are asymptomatic.
|
From page 136... ...
They can also lead to important refinements in a nonhuman primate model so that it better reflects the situation in humans. An example is high- versus low-dose mucosal challenge with SIV and SHIV in macaques.
|
From page 137... ...
2007. Old rhesus macaques treated with interleukin-7 show increased TREC levels and respond well to influenza vaccination.
|
From page 138... ...
2011. Both innate and adaptive immunity mediate protective immunity against hepatitis C virus infection in chimpanzees.
|
From page 139... ...
2005. Adaptive immune responses in acute and chronic hepatitis C virus infection.
|
From page 140... ...
1997. Evolution of envelope-specific antibody responses in monkeys experimentally infected or immunized with simian immunodeficiency virus and its association with the development of protective immunity.
|
From page 141... ...
2008. Genetic immunisation by liver stage antigen 3 protects chimpanzees against malaria despite low immune responses.
|
From page 142... ...
2007. MIC gene polymorphism and haplotype diversity in rhesus macaques.
|
From page 143... ...
1987. T-cell responses to human immunodeficiency virus (HIV)
|
From page 144... ...
2009. Antiviral CD8+ T cells in the genital tract control viral replication and delay progression to AIDS after vaginal SIV challenge in rhesus macaques immunized with virulence attenuated SHIV 89.6.
|
From page 145... ...
2011. Biological challenges and technological opportunities for respiratory syncytial virus vaccine development.
|
From page 146... ...
2009. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge.
|
From page 147... ...
2000. Simian immunodeficiency virus infection of monkeys as a model system for the study of AIDS pathogenesis, treatment, and prevention.
|
From page 148... ...
2005. Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses.
|
From page 149... ...
2009b. Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV 1.
|
From page 150... ...
2009. Is the gut the major source of virus in early simian immunodeficiency virus infection?
|
From page 151... ...
1995. Viral factors determine progression to AIDS in simian immunodeficiency virus-infected newborn rhesus macaques.
|
From page 152... ...
2009. Simian varicella virus infection of rhesus macaques recapitulates essential features of varicella zoster virus infection in humans.
|
From page 153... ...
coronavirus S protein neutralizes the virus in a rhesus macaque SARS model. J Infect Dis 203:1574-1581.
|
From page 154... ...
2008. The use of nonhuman primate models in HIV vaccine development.
|
From page 155... ...
2006. Systemic immunization with an ALVAC-HIV-1/protein boost vaccine strategy protects rhesus macaques from CD4+ T-cell loss and reduces both systemic and mucosal simian human immunodeficiency virus SHIVKU2 RNA levels.
|
From page 156... ...
2003. Potent, persistent induction and modulation of cellular immune responses in rhesus macaques primed with Ad5hr-simian immunodeficiency virus (SIV)
|
From page 157... ...
2008. Case of yellow fever vaccine–associated viscerotropic disease with prolonged viremia, robust adaptive immune responses, and polymorphisms in CCR5 and RANTES genes.
|
From page 158... ...
2009. Hepatitis C virus versus innate and adaptive immune responses: A tale of coevolution and coexistence.
|
From page 159... ...
1999. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes.
|
From page 160... ...
2003. Effect of humoral immune responses on controlling viremia during primary infection of rhesus monkeys with simian immunodeficiency virus.
|
From page 161... ...
2009. Toward an AIDS vaccine: Lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts.
|
From page 162... ...
2001. Determinants of viral clearance and persistence during acute hepatitis C virus infection.
|
From page 163... ...
2003. Control of viremia and prevention of simian-human immunodeficiency virus induced disease in rhesus macaques immunized with recombinant vaccinia viruses plus inactivated simian immunodeficiency virus and human immunodeficiency virus type 1 particles.
|
From page 164... ...
2009. Partial protection of Simian immunodeficiency virus (SIV)
|
From page 165... ...
2011. Cross-clade HIV-1 neutralizing antibodies induced with V3-scaffold protein immunogens following priming with gp120 DNA.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.