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Induction of long-term protective effects against heterologous challenge in SIVhu-infected macaques
F Villinger1, W M Switzer, B S Parekh
1Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA. fvillin@emory.edu
Abstract:
A group of three rhesus macaques were inoculated with SIV isolated from a human (SIVhu) accidentally exposed and infected with SIVsm. Extensive sequence analyses of SIVhu obtained from the human and macaques following infection indicated the presence of truncated nef. Not only did nef fail to repair itself in vivo postinfection (p.i.), but instead, further mutations added additional stop codons with increasing time p.i. Infection of these animals was associated with minimal acute viral replication, followed by undetectable plasma viral loads and only intermittent PCR detection up to 5 years p.i. The three SIVhu infected and three control monkeys were then challenged with the heterologous highly pathogenic SHIV89.6p. All three controls became infected and showed rapid declines in peripheral CD4(+) lymphocytes, disease, and death at 10 and 32 weeks p.i., respectively. In contrast, all three animals previously infected with SIVhu are healthy and exhibit stable CD4(+) lymphocyte levels and undetectable plasma viral loads at >20 months post-SHIV89. 6p challenge. Only transient, low levels of SHIV replication were noted in these animals. Whereas responses to SIVgag/pol were noted, no evidence for SIV/SHIV envelope cross-reactivity was detected by antibody or CTL analyses, suggesting that the protective immune mechanisms to the heterologous challenge isolate were most likely not directed to envelope but rather to other viral determinants.
Insights
Infection with a truncated nef gene in simian immunodeficiency virus (SIVhu) protected macaques from a pathogenic simian-human immunodeficiency virus (SHIV) challenge. This suggests nef gene integrity is crucial for SIV pathogenesis.
Area of Science:
- Virology
- Immunology
- Primate Models
Background:
- Simian immunodeficiency virus (SIV) infection in rhesus macaques serves as a model for human immunodeficiency virus (HIV) research.
- Truncated nef genes in SIV have been associated with attenuated viral replication and disease progression.
Purpose of the Study:
- To investigate the in vivo behavior and pathogenic potential of a human-derived SIV (SIVhu) with a truncated nef gene.
- To assess the protective immunity conferred by prior SIVhu infection against a highly pathogenic simian-human immunodeficiency virus (SHIV) challenge.
Main Methods:
- Inoculation of rhesus macaques with SIVhu and subsequent sequence analysis to monitor nef gene integrity.
- Challenge of SIVhu-infected and control macaques with the pathogenic SHIV89.6p.
- Monitoring of viral loads, CD4+ T-lymphocyte counts, and clinical signs post-challenge.
Main Results:
- SIVhu exhibited minimal replication, undetectable plasma viral loads, and stable CD4+ counts in infected macaques for up to 5 years.
- Control macaques succumbed to SHIV89.6p infection with rapid CD4+ decline and disease.
- SIVhu-infected macaques showed complete protection against SHIV89.6p, maintaining stable CD4+ counts and undetectable viral loads for over 20 months.
Conclusions:
- The truncated nef gene in SIVhu appears to induce a protective immune response against heterologous SHIV challenge.
- Protection is likely mediated by non-envelope viral determinants, as no cross-reactivity was observed.
- Nef gene integrity is critical for SIV pathogenesis and viral control.