Animal models for HIV/AIDS research

Hatziioannou, Théodora; Evans, David T.

doi:10.1038/nrmicro2911

Cited by 288 publications

(315 citation statements)

References 203 publications

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“…Although macaques seem to be more responsive than humans in immunogenicity analyses, the rhesus macaque model at least allows a ranking of the immunogenicities of different vectors (20). Therefore, despite additional limitations, such as differences in the configuration of major histocompatibility complex class I (MHC-I) loci (21), monkey trials are instrumental in evaluating the numerous vaccine regimens and help in the design of human clinical trials. Importantly, the cellular immune responses observed in humans in the EV02 study were remarkably similar to those obtained in macaques immunized with the same DNA and NYVAC vaccine candidates and according to the same regimen (22), which supports the value of the rhesus macaque model.…”

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confidence: 99%

Potential To Streamline Heterologous DNA Prime and NYVAC/Protein Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens

Asbach

Kliche

Köstler

et al. 2016

J Virol

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In a follow-up to the modest efficacy observed in the RV144 trial, researchers in the HIV vaccine field seek to substantiate and extend the results by evaluating other poxvirus vectors and combinations with DNA and protein vaccines. Earlier clinical trials (EuroVacc trials 01 to 03) evaluated the immunogenicity of HIV-1 clade C GagPolNef and gp120 antigens delivered via the poxviral vector NYVAC. These showed that a vaccination regimen including DNA-C priming prior to a NYVAC-C boost considerably enhanced vaccine-elicited immune responses compared to those with NYVAC-C alone. Moreover, responses were improved by using three as opposed to two DNA-C primes. In the present study, we assessed in nonhuman primates whether such vaccination regimens can be streamlined further by using fewer and accelerated immunizations and employing a novel generation of improved DNA-C and NYVAC-C vaccine candidates designed for higher expression levels and more balanced immune responses. Three different DNA-C prime/NYVAC-C؉ protein boost vaccination regimens were tested in rhesus macaques. All regimens elicited vigorous and well-balanced CD8 ؉ and CD4 ؉ T cell responses that were broad and polyfunctional. Very high IgG binding titers, substantial antibody-dependent cellular cytotoxicity (ADCC), and modest antibody-dependent cell-mediated virus inhibition (ADCVI), but very low neutralization activity, were measured after the final immunizations. Overall, immune responses elicited in all three groups were very similar and of greater magnitude, breadth, and quality than those of earlier EuroVacc vaccines. In conclusion, these findings indicate that vaccination schemes can be simplified by using improved antigens and regimens. This may offer a more practical and affordable means to elicit potentially protective immune responses upon vaccination, especially in resource-constrained settings. IMPORTANCEWithin the EuroVacc clinical trials, we previously assessed the immunogenicity of HIV clade C antigens delivered in a DNA prime/NYVAC boost regimen. The trials showed that the DNA prime crucially improved the responses, and three DNA primes with a NYVAC boost appeared to be optimal. Nevertheless, T cell responses were primarily directed toward Env, and humoral responses were modest. The aim of this study was to assess improved antigens for the capacity to elicit more potent and balanced responses in rhesus macaques, even with various simpler immunization regimens. Our results showed that the novel antigens in fact elicited larger numbers of T cells with a polyfunctional profile and a good Env-GagPolNef balance, as well as high-titer and Fc-functional antibody responses. Finally, comparison of the different schedules indicates that a simpler regimen of only two DNA primes and one NYVAC boost in combination with protein may be very efficient, thus showing that the novel antigens allow for easier immunization protocols.

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confidence: 99%

Potential To Streamline Heterologous DNA Prime and NYVAC/Protein Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens

Asbach

Kliche

Köstler

et al. 2016

J Virol

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“…Macaques infected with SIV mac serve as the principal animal model for pathogenic infection of humans with human immunodeficiency virus type 1 (HIV-1), and understanding the mechanisms that underlie the dichotomy between natural-and nonnatural-host SIV infection may lead to a better understanding of mechanisms of disease progression and AIDS pathogenesis. Because SIV mac viruses arose from cross-species transfers of SIV smm from SM to RM, species-matched virus-host interactions in SM and RM serve as an ideal platform for comparative analysis (1).…”

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confidence: 99%

Dualtropic CXCR6/CCR5 Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in Natural versus Pathogenic Hosts of SIV

Elliott

Wetzel

Francella

et al. 2015

J Virol

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Natural-host sooty mangabeys (SM) infected with simian immunodeficiency virus (SIV) exhibit high viral loads but do not develop disease, whereas infection of rhesus macaques (RM) causes CD4؉ T cell loss and AIDS. Several mechanisms have been proposed to explain these divergent outcomes, including differences in cell targeting, which have been linked to low expression of the canonical SIV entry receptor CCR5 on CD4 ؉ T cells of SM and other natural hosts. We previously showed that infection and high-level viremia occur even in a subset of SM that genetically lack functional CCR5, which indicates that alternative entry coreceptors are used by SIV in vivo in these animals. We also showed that SM CXCR6 is a robust coreceptor for SIV smm in vitro. Here we identify CXCR6 as a principal entry pathway for SIV in SM primary lymphocytes. We show that ex vivo SIV infection of lymphocytes from CCR5 wild-type SM is mediated by both CXCR6 and CCR5. In contrast, infection of RM lymphocytes is fully dependent on CCR5. These data raise the possibility that CXCR6-directed tropism in CCR5-low natural hosts may alter CD4 ؉ T cell subset targeting compared with that in nonnatural hosts, enabling SIV to maintain high-level replication without leading to widespread CD4 ؉ T cell loss.

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“…The most widely utilized primate model for investigating lentiviral infection and disease is the SIV infecting rhesus macaques (SIVmac), with rhesus macaques of Indian origin being the best characterized species. 38 Rhesus macaques are not natural hosts of SIV in the wild; rather, SIVmac emerged from cross-species transmission events in US primate centers and likely originated from infected sooty mangabeys. 39,40 The adaptations allowing the virus to stably infect rhesus macaques likely occurred as a result of serial passages of the virus through multiple animals.…”

Section: Objectivementioning

confidence: 99%

A Biological "Arms Race": APOBEC3F Diversity and its Influence on Lentiviral Resistance

Tank¹

2015

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restriction factors are implicated in long-term evolutionary "arms races," in which viral antagonists drive the evolution of host proteins, and vice versa. consequently, restriction factors are remarkably variable, displaying polymorphism within species and divergence between species as a result of positive selection. this paper investigates diversity in the apobec3f (a3f) restriction factors of old world primates in order to determine whether they display evidence of involvement in an evolutionary "arms race." we speculated that genetic variability in a3f could reflect evolutionary conflict with the vif proteins of primate lentiviruses, which are known to enhance viral replication by binding and degrading host a3 proteins. a3fs of several old world primate species were genotyped, and the sequences revealed both intra-species diversity and inter-species divergence. representative rhesus macaque (macaca mulatta) sequences were cloned and tested for sensitivity to vifs from various simian immunodeficiency viruses (sivs). evolution of a3f in the rhesus lineage is not due to selection by sivs, but may reflect antagonism by another retrovirus. 1 The causative agent was soon discovered to be a lentivirus, classified as Human Immunodeficiency Virus Type 1 (HIV-1).2,3 HIV-1 and its close relative HIV Type 2 (HIV-2) arose in human populations as a result of cross-species transmission events from natural simian hosts of the Simian Immunodeficiency Viruses (SIVs). The closest simian relative of HIV-1 is the strain naturally infecting chimpanzees (SIVcpz), 4 while the closest simian relative of HIV-2 is the strain naturally infecting sooty mangabeys (SIVsm).5 Over 40 species-specific SIVs have since been identified in nonhuman primate species. A fraction of these infections result in immunodeficiency in the host species, while most are nonpathogenic in their natural hosts. 6 The SIV of a given primate species cannot readily infect a different species without undergoing numerous adaptations. Part of this adaptation process involves evading host antiviral proteins known as restriction factors. Restriction factors are host proteins that utilize numerous mechanisms to interfere with viral infections as part of the innate immune response. Some interact directly with viral factors, while others make the cellular environment unsuitable for sustained viral replication.7 These defensive genes are subject to relatively rapid evolution under the selective pressure of viral counter-restriction mechanisms, and variants that confer greater fitness to the host during a viral outbreak will become fixed in a population much faster than would normally be expected as a result of genetic drift alone. The virus, in turn, can adapt to infect the host carrying these more fit alleles, creating a new selective pressure on the host. Thus, over evolutionary time, a comparatively large number of non-synonymous, or protein-altering, mutations will be evident in genes that have participated in these virus-host "arms races." 8 Genes can be examined for e...

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Animal models for HIV/AIDS research

Cited by 288 publications

References 203 publications

Potential To Streamline Heterologous DNA Prime and NYVAC/Protein Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens

Potential To Streamline Heterologous DNA Prime and NYVAC/Protein Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens

Dualtropic CXCR6/CCR5 Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabey Primary Lymphocytes: Distinct Coreceptor Use in Natural versus Pathogenic Hosts of SIV

A Biological "Arms Race": APOBEC3F Diversity and its Influence on Lentiviral Resistance

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