AIDSWEEKLY Plus; Monday, February 1, 1999
Daniel J. DeNoon, Senior Editor

A steady decline in his CD4 T-cell count has forced a U.S. man naturally infected with nef-deleted HIV - the same deletion used in a prototype AIDS vaccine - to begin taking antiretroviral therapy after 15 years of asymptomatic infection.

Deletion of the nef gene from simian immunodeficiency virus (SIV) prototype vaccines offer the most complete protection against virulent challenge of any vaccine approach yet tested. Vaccine developer Ronald C. Desrosiers and colleagues first reported the patient with natural nef-deleted HIV-1 infection in 1995 (Kirchhoff, F. et al., N Engl J Med 1995 Jan 26;332(4):228-32). It later became apparent that a blood donor in Sydney, Australia, and several recipients of his blood all had been infected with a natural nef-deleted HIV-1 mutant (the Sydney Blood Bank Cohort or SBBC).

The U.S. man and all of the SBBC members have been healthy and without symptoms of AIDS for 13 to 17 years. Indeed, as of late 1998 many of these patients still had robust HIV specific cytotoxic T- lymphocyte (CTL) activity similar to that seen in animals protected by prototype vaccines.

But follow-up of these patients suggested that at least some may be showing signs of disease progression (see AIDS Weekly Plus, December 28, 1998; a publication by SBBC team member Jennifer Learmont is expected to appear soon). Now the same thing appears to be happening to the U.S. patient.

"We have recently seen declining CD4 T-lymphocyte counts in a man with long-term, nonprogressive infection with only nef-deleted forms of HIV-1," reported Thomas C. Greenough and John L. Sullivan of the University of Massachusetts and Ronald C. Desrosiers of the New England Regional Primate Research Center.

Greenough et al. reported the data in a letter to the New England Journal of Medicine ("Declining CD4 T-Cell Counts in a Person Infected with nef-Deleted HIV-1," N Engl J Med 1999 Jan 21;340(3):236-7).

The patient has had only one positive culture for HIV since 1985. The mutant HIV strain with which he was infected does not seem to have reverted to wild-type form: repeated DNA analyses show that the nef deletion (a 236 bp deletion in the nef region of the genome and a 134 bp deletion in the nef region overlapping the long terminal repeat) has remained stable.

Despite the deletion, which greatly reduces the virus's ability to replicate, the patient obviously was receiving constant stimulation by HIV antigens. He maintains strong CD4 T-lymphoproliferative responses to HIV-1 antigens and has consistently increased levels of activated CD8(+) T cells. His plasma RNA viral load remains undetectable (<50 copies/mL) and his levels of viral DNA in peripheral blood mononuclear cells (PBMC) remains low (20 to 164 copies per million CD4 cells).

But in 1997 it became obvious that his CD4 counts were declining: respective measures of 713 and 666 cells/(micro)L in March and October 1994 dropped to 579 and 410 cells/(micro)L in January and October 1997. In late March, 1998 his CD4 count was 288 cells/(micro)L and by late June 1998 it had further declined to 261 cells/(micro)L.

"The patient began an highly active antiretroviral regimen (zidovudine [AZT], lamivudine [3TC], and nevirapine) immediately after his June 1998 visit, and CD4 T-cell counts have subsequently increased," Greenough et al. noted.

Evaluation in mid-September 1998 showed that his T-cell count had increased to 328 cells/(micro)L. Viral load remains undetectable, and measures of anti-HIV immune responses remain strong.

"Various hypotheses could explain this disease progression," Greenough et al. suggested. They offered several hypotheses:

* Even though it is so low as to be undetectable by current assays, viral replication may be sufficient to directly or indirectly kill CD4 T cells.

* Immune responses to HIV are deleting T cells carrying the virus.

* Thymic regenerative capacity may have declined to a point at which T-cell replacement cannot keep pace with HIV mediated T-cell destruction.

Although further attenuation of HIV is possible, it is unclear whether such a weak live-virus vaccine would be able to stimulate immune responses strong enough to protect against disease.

The corresponding authors of the NEJM letter are Thomas C. Greenough and John L. Sullivan, University of Massachusetts Medical School, Worcester, MA 01605; and Ronald C. Desrosiers, New England Regional Primate Research Center, Southborough, MA 01772.

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