AIDSWEEKLY Plus, Monday, 30 June 1997
Daniel J. DeNoon, Senior Editor
Attenuation of HIV-1 by deletion of its nef gene retards but does not prevent CD4(+) T-cell loss in a mouse model of HIV infection.
By far, the most effective AIDS vaccine prototype is a live simian immunodeficiency virus (SIV) vaccine attenuated by deletions in the nef, vpr, and LTR genes. The new findings may slow the growing support for human tests of a similarly attenuated live HIV vaccine.
"The importance of nef ... seems to be less than that implied by the finding of long-term survivors with spontaneous nef deletions or the absence of simian AIDS in monkeys infected with nef-deficient simian immunodeficiency virus type 1," wrote Richard J. Gulizia of the Scripps Research Institute and colleagues.
Gulizia et al. reported their findings in the journal Virology ("Deletion of nef Slows but Does Not Prevent CD4 Positive T-Cell Depletion in Human Immunodeficiency Virus Type 1 Infected Human-PBL-SCID Mice," Virology, 1997;71(5):4161-4).
The researchers noted that the HIV protein Nef contributes to HIV pathogenesis by down regulation of cellular CD4 expression, disruption of T-cell signals, and enhancement of viral infectivity. In addition, the protein modulates host immune responses by affecting expression of major histocompatibility complex (MHC) class I antigen and production of immunomodulatory cytokines.
Because of evidence that Nef is more important to some HIV-1 phenotypes than to others, Gulizia et al. used four different HIV-1 molecular clones in their experiments: the T- cell tropic isolates SF2 and R9, the macrophage-tropic isolate R9.BaL, and the dual-tropic isolate 89.6.
The viruses - and nef-deleted mutants of each - were used to infect severe combined immunodeficient mice repopulated with human peripheral blood lymphocytes (hu-PBL-SCID mice).
"These studies show that deletion of the nef accessory gene from four different HIV-1 isolates that differed in cell tropism, cytopathicity, and replication kinetics led, in each isolate, to a slower course of virus replication and a delay in CD4(+) T-cell depletion in infected hu-PBL-SCID mice," Gulizia et al. wrote. "Deletion of nef caused a major reduction in the infectivity of only one of the four HIV-1 isolates examined, SF2."
Deletion of nef delayed peak levels of HIV-1 RNA by only one to two weeks. SCID mice are unable to mount an immune response to HIV. But could a similar delay in infection kinetics give normal immune systems enough time to mount an effective anti-HIV response? If so, this could explain the discrepancy between the effects of nef-deleted mutants in SCID mice and their effects in human long-term nonprogressors and in the monkeys that received live attenuated vaccines.
"A vigorous and sustained immune response to nef-defective viruses following an attenuated primary infection of humans or primates may explain these apparently discordant results," Gulizia et al. suggested.
They concluded that Nef may be less important for highly pathogenic, dual tropic HIV-1 isolates than for less virulent strains of the virus.
This work was supported by National Institutes of Health grant AI-29182.
The corresponding author for this study is Donald E. Mosier, Department of Immunology-IMM7, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, California 92037. Phone: (619) 784-9121. Fax: (619) 784-9190. Email: dmosier@scripps.edu.
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