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Viral factors determine progression to AIDS in simian immunodeficiency virus-infected newborn rhesus macaques
M L Marthas1, K K van Rompay, M Otsyula
1California Regional Primate Research Center, University of California, Davis 95616, USA.
Abstract:
To evaluate how viral variants may affect disease progression in human pediatric AIDS, we studied the potential of three simian immunodeficiency virus (SIV) isolates to induce simian AIDS in newborn rhesus macaques. The three virus isolates were previously shown to range from pathogenic (SIVmac251 and SIVmac239) to nonpathogenic (SIVmac1A11) when inoculated intravenously into juvenile and adult rhesus macaques. Six newborn macaques inoculated with pathogenic, uncloned SIVmac251 developed persistent, high levels of cell-associated and cell-free viremia, had no detectable antiviral antibodies, and had poor weight gain; these animals all exhibited severe clinical disease and pathologic lesions diagnostic for simian AIDS and were euthanatized 10 to 26 weeks after inoculation. Two newborns inoculated with pathogenic, molecularly cloned SIVmac239 developed persistent high virus load in peripheral blood, but both animals had normal weight gain and developed antiviral antibodies. One of the SIVmac239-infected neonates exhibited pathologic lesions diagnostic for SAIDS and was euthanatized at 34 weeks after inoculation; the other SIVmac239-infected neonate remained alive and exhibited no significant clinical disease for more than 1 year after inoculation. In contrast, three newborn rhesus macaques inoculated with the nonpathogenic molecular clone, SIVmac1A11, had transient, low-level viremia, seroconverted by 10 weeks after inoculation, had normal weight gain, and remained healthy for over 1 year. These results indicate that (i) newborn rhesus macaques infected with an uncloned, virulent SIVmac isolate have a more rapid, fulminant disease course than do adults inoculated with the same virus, (ii) the most rapid disease progression is associated with lack of a detectable humoral immune response in SIV-infected infant macaques, (iii) a molecularly cloned, attenuated SIV isolate is nonpathogenic in neonatal macaques, and (iv) SIV-infected neonatal macaques exhibit patterns of infection, virus load, and disease progression similar to those observed in human immunodeficiency virus-infected children. This SIV/neonatal rhesus model of pediatric AIDS provides a rapid, sensitive model with which to compare the virulence of SIV isolates and to study the mechanisms underlying the differences in disease progression in human immunodeficiency virus-infected infants.
Insights
Newborn macaques infected with simian immunodeficiency virus (SIV) showed rapid simian AIDS progression, especially without antiviral antibodies. This SIV model in neonates mimics pediatric AIDS, aiding research into viral variants and disease mechanisms.
Area of Science:
- Veterinary Virology
- Immunology
- Pathology
Background:
- Pediatric AIDS research requires models that mimic human immunodeficiency virus (HIV) infection in infants.
- Simian immunodeficiency virus (SIV) infection in rhesus macaques is a model for HIV/AIDS.
- Neonatal SIV infection models are crucial for understanding early disease progression.
Purpose of the Study:
- To evaluate how different simian immunodeficiency virus (SIV) isolates affect disease progression in newborn rhesus macaques.
- To establish a neonatal rhesus macaque model for pediatric AIDS research.
- To compare the virulence of pathogenic and nonpathogenic SIV isolates in neonates.
Main Methods:
- Inoculation of newborn rhesus macaques with three distinct SIV isolates: pathogenic uncloned SIVmac251, pathogenic cloned SIVmac239, and nonpathogenic cloned SIVmac1A11.
- Monitoring of viremia, antiviral antibody response, weight gain, clinical signs, and pathological lesions.
- Assessment of disease progression and comparison between different SIV isolates and age groups.
Main Results:
- Newborns infected with uncloned SIVmac251 developed rapid, severe simian AIDS with high viremia and no antibodies.
- Newborns infected with cloned SIVmac239 showed variable disease, with one developing simian AIDS and the other remaining healthy.
- Newborns infected with nonpathogenic SIVmac1A11 exhibited mild, transient infection with normal development and health.
Conclusions:
- Newborn macaques infected with virulent SIV show faster disease progression than adults.
- Lack of detectable antiviral antibodies correlates with rapid disease progression in SIV-infected infants.
- The SIV/neonatal rhesus macaque model effectively replicates key aspects of pediatric AIDS, enabling study of viral virulence and disease mechanisms.