Related Experiment Videos
Characterization of molecularly cloned simian-human immunodeficiency viruses causing rapid CD4+ lymphocyte depletion
G B Karlsson1, M Halloran, J Li
1Division of Human Retrovirology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Abstract:
In vivo passage of a chimeric simian-human immunodeficiency virus (SHIV-89.6) expressing the human immunodeficiency virus type 1 (HIV-1) tat, rev, vpu, and env genes generated pathogenic viruses (SHIV-89.6P) inducing rapid CD4+ lymphocyte depletion and AIDS-like illness in rhesus monkeys (K. Reimann, J. T. Li, R. Veazey, M. Halloran, I.-W. Park, G. B. Karlsson, J. Sodroski, and N. L. Letvin, J. Virol. 70:6922-6928, 1996). To characterize the molecular changes responsible for this increase in virulence, infectious proviral clones of SHIV-89.6P isolates were derived. Viruses generated from some of these clones caused a rapid and profound decline of CD4+ lymphocytes in a high percentage of inoculated monkeys. Nucleotide changes potentially responsible for the increased virulence of SHIV-89.6P were limited to the env, tat, or long terminal repeat sequences, with most of the observed changes in env. Nucleotide changes in env altered 12 amino acids in the gp120 and gp41 exterior domains, and a 140-bp deletion in env resulted in the substitution of the carboxyl terminus of the SIVmac gp41 glycoprotein for that of the HIV-1 gp41 glycoprotein. The availability of pathogenic proviral clones should facilitate dissection of the molecular determinants of SHIV-89.6P virulence.
Insights
Pathogenic simian-human immunodeficiency virus (SHIV-89.6P) causes rapid CD4+ T-cell depletion in monkeys. Molecular analysis identified key genetic changes, primarily in the env gene, responsible for this increased virulence.
Area of Science:
- Virology
- Immunology
- Pathogenesis
Background:
- Chimeric simian-human immunodeficiency virus (SHIV-89.6) expressing human immunodeficiency virus type 1 (HIV-1) genes was previously developed.
- In vivo passage of SHIV-89.6 in rhesus monkeys generated pathogenic SHIV-89.6P, causing rapid CD4+ lymphocyte depletion and AIDS-like illness.
Purpose of the Study:
- To characterize the molecular changes responsible for the increased virulence of SHIV-89.6P.
- To identify specific genetic alterations contributing to SHIV-89.6P pathogenesis.
Main Methods:
- Derivation of infectious proviral clones from SHIV-89.6P isolates.
- Analysis of nucleotide sequences to identify changes in env, tat, and long terminal repeat (LTR) regions.
- Assessment of viral pathogenicity in rhesus monkeys inoculated with viruses from derived clones.
Main Results:
- Viruses derived from some SHIV-89.6P clones induced rapid and profound CD4+ lymphocyte decline in rhesus monkeys.
- Molecular changes associated with increased virulence were localized to env, tat, or LTR sequences.
- Most observed changes were in the env gene, including 12 amino acid alterations in gp120/gp41 and a 140-bp deletion in env leading to gp41 carboxyl terminus substitution.
Conclusions:
- The study successfully derived pathogenic SHIV-89.6P proviral clones.
- Specific nucleotide changes, particularly within the env gene, are critical determinants of SHIV-89.6P virulence.
- These pathogenic clones provide a valuable tool for dissecting the molecular mechanisms underlying SHIV-89.6P pathogenesis.