Important note: Information in this article was accurate in May 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, May 17, 1999
Daniel J. DeNoon, Senior Editor
The new virus affects monkeys much like HIV affects humans. Like its predecessors, the virus is a recombinant chimeric virus created by wrapping the SIV core in the HIV envelope to make a simian/human immunodeficiency virus (SHIV).
Previous pathogenic SHIVs are X4 viruses, tropic for the CXCR4 (X4) coreceptor or R5X4 viruses, tropic for both the CCR5 (R5) and X4 coreceptors. Disease caused by these viruses is more like that seen in late-stage HIV infection and is characterized by the precipitous loss of peripheral CD4(+) T cells.
A new, pathogenic R5 SHIV (SHIV[SF162P']) causes a rapid depletion of intestinal CD4(+) cells in monkeys, but only a gradual depletion of peripheral CD4(+) cells - much like the pathogenesis of SIV infection in macaques. A new X4 SHIV (SHIV[SF33A.2']) causes a profound loss of peripheral, but not intestinal, CD4(+) cells.
"These results suggest a critical role of coreceptor utilization in viral pathogenesis and provide a reliable in vivo model for preclinical examination of HIV-1 vaccines and therapeutic agents in the context of the HIV-1 envelope protein," wrote Janet M. Harouse of the Aaron Diamond AIDS Research Center (ADARC), New York, and colleagues.
Harouse et al. reported their findings in the journal Science ("Distinct Pathogenic Sequela in Rhesus Macaques Infected with CCR5 or CXCR4 Utilizing SHIVs," Science 1999 Apr 30;284(5415):816-9.
The researchers noted that pathogenic SHIV viruses being used to evaluate candidate HIV vaccines in the macaque model have a major drawback: their kinetics of infection differ significantly from both pathogenic SIV infection and from HIV infection. They hypothesized that this was due to the X4 or R5X4 tropism of extant SHIVs.
The great majority of HIV transmissions are by R5 viruses, and R5 strains predominate throughout the asymptomatic phase of HIV disease. Coincident with the dramatic loss of CD4(+) T cells that heralds AIDS, there is a change to predominance of X4 virus.
"Development of a pathogenic R5-specific SHIV might facilitate the preclinical analysis of candidate antiviral compounds and vaccines and reveal aspects of viral pathogenesis not observed in previously described animal model systems," Harouse et al. wrote.
They set out to do just that. Using the same approach that was used to create other pathogenic SHIVs, they inoculated rhesus macaques with a molecular clone of the nonpathogenic R5 SHIV[SF162] and then gave blood and bone- marrow transfusions from these animals to naive macaques. Successive in vivo passage of this virus, now dubbed SHIV[SF162'], yielded the desired pathogenic R5 virus.
By a similar process the researchers developed the pathogenic X4 SHIV[SF33A.2'] from nonpathogenic SHIV[SF33A.2].
"The availability of pathogenic R5- and X4-specific envelope SHIVs that replicate with similar kinetics and to comparable levels provides the tools that are necessary to answer important questions related to viral pathogenesis, transmission, adaptation, and evolution," Harouse et al. wrote. "Additionally, the SHIV[SF162P] and SHIV[SF33A] animal model system described will be instrumental in addressing the long debated issues of preferential R5 transmission and phenotypic switch."
This work was supported in part by National Institutes of Health grants.
The corresponding author for this study is Cecilia Cheng- Mayer, Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Avenue, 7th Floor, New York, NY 10016. Email: <cmayer@adarc.org>.
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