Correspondence

Declining CD4 T-Cell Counts in a Person Infected with nef-Deleted HIV-1

N Engl J Med 1999; 340:236-237January 21, 1999

Article

To the Editor:

We have recently seen declining CD4 T-lymphocyte counts in a man with long-term, nonprogressive infection with only nef-deleted forms of human immunodeficiency virus type 1 (HIV-1). This patient was described in the January 26, 1995, issue of the Journal. 1 Although he has remained asymptomatic for more than 15 years, a decline in the number of CD4 T cells first became apparent in 1997 (Table 1Table 1Immunologic and Virologic Measurements, 1994–1998.). Plasma viral RNA has remained undetectable. Since 1985, all efforts to culture virus, except one in 1994, have failed. Levels of viral DNA in peripheral-blood mononuclear cells have also remained low, ranging from 20 to 164 copies per 10⁶ CD4 T cells.

Strong CD4 T-lymphocyte proliferative responses to HIV-1 gag antigen and HIV-1 specific cytotoxic T-lymphocyte activity, along with increased levels of activated (HLA-DR–positive) CD8 T cells, have persisted throughout the period of observation. Together, these findings indicate potent antigenic stimulation, despite undetectable levels of plasma viral RNA (<50 copies per milliliter).

Sequencing of viral DNA in peripheral-blood mononuclear cells obtained in March 1998 revealed a deletion of 236 bp in the region that is uniquely nef and a deletion of 134 bp in the region of nef that overlaps U3 in the long terminal repeat. No full-length nef sequences were detected. There were no duplications of NF-κB binding elements or other changes in the long terminal repeat that could be considered compensatory in nature. The deletions observed in March 1998 were similar to those in samples obtained from the patient in 1997, 1994, and 1993, as reported earlier,1 and were similar to the deletions observed in the HIV-1 isolate obtained in 1994.

Various hypotheses could explain this disease progression. It is possible that viral replication (albeit at levels that cannot be detected by current plasma viral-RNA assays) is sufficient to cause the loss of CD4 T cells through a direct virus-induced cytopathic effect, strong cellular immune responses to virus-infected cells, or indirect mechanisms. It is also possible that thymic regenerative capacity has declined to a point at which the production of CD4 T cells cannot match the destruction.

The patient began a highly active antiretroviral regimen (zidovudine, lamivudine, and nevirapine) immediately after his June 1998 visit, and CD4 T cell counts have subsequently increased. Plasma viral RNA has remained undetectable, and the numbers of cell-associated DNA copies have remained low. Activated CD8 T-cell populations have remained elevated, suggesting the persistence of stimulating antigen.

Thomas C. Greenough, M.D.
John L. Sullivan, M.D.
University of Massachusetts Medical School, Worcester, MA 01605

Ronald C. Desrosiers, Ph.D.
New England Regional Primate Research Center, Southborough, MA 01772

1 References

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   Full Text | Web of Science | Medline

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