Correspondence

Cytotoxic-T-Cell Responses in Early HIV-1 Infection

N Engl J Med 1998; 338:622-623February 26, 1998

Article

To the Editor:

Musey et al. (Oct. 30 issue)1 suggest that their study shows that cytotoxic T lymphocytes have a modest effect of reducing the viral load, on the basis of the cross-sectional inverse correlation between human immunodeficiency virus type 1 (HIV-1) Env-specific cytotoxic T lymphocytes and plasma HIV RNA. This correlation may instead be due to the fact that the viral load is an inverse measure of the number of CD4+ lymphocytes, which help CD8+ cytotoxic T cells maintain responsiveness. This possibility could be investigated by adjusting for the CD4+ count when assessing the association between the cytotoxic-T-lymphocyte response and the viral load. The association between HIV-1 Env-specific cytotoxic T lymphocytes and plasma HIV RNA was weakest soon after seroconversion, when the association between HIV-1 Env-specific cytotoxic T lymphocytes and the CD4+ count was also weakest. The authors' conclusion that “the induction of memory cytotoxic T lymphocytes, particularly those specific for Env, helps control viral replication” seems unwarranted, since a higher level of Pol-specific cytotoxic T lymphocytes was associated with a higher viral load in peripheral-blood mononuclear cells (Table 2 in the article) and, when reduced to a binary variable, with higher plasma HIV RNA levels (Table 3 in the article).

A failure to adjust for the initial CD4+ lymphocyte count may also explain the relation between a higher level of HIV-1 Env-specific cytotoxic T lymphocytes and a longer time to a decrease in the CD4+ count to a level below 300 per cubic millimeter. It would also be helpful to know the relation between cytotoxic T lymphocytes with specificities other than Env and a fall in the CD4+ count to a level below 300 per cubic millimeter, again adjusted for the initial CD4+ lymphocyte count.

Andrew N. Phillips, Ph.D.
Royal Free Hospital School of Medicine, London NW3 2PF, United Kingdom

1 References

1
Musey L, Hughes J, Schacker T, Shea T, Corey L, McElrath MJ. Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection. N Engl J Med 1997;337:1267-1274
Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Since absolute CD4+ lymphocyte counts do not determine helper function, and because T-helper–cell dysfunction occurs in persons with early infection and relatively normal CD4+ T-cell counts (unpublished data), we did not adjust for CD4+ counts when we examined the association between HIV-1–specific cytotoxicity and viral load in our study. Nonetheless, in response to Dr. Phillips's comments, we compared the univariate analysis with the multivariate analysis, adjusting for the CD4+ lymphocyte count (Table 1Table 1Association of Cytotoxic-T-Lymphocyte Responses with Viral Load and CD41 T-Cell Count in Early HIV-1 Infection.). Our findings are unchanged and indicate an inverse correlation between HIV-1 Env-specific cytotoxic T lymphocytes and plasma HIV-1 RNA. Indeed, the correlation was weakest just after infection, and this finding may be explained by the large fluctuation in the viral load during this period.1 Higher levels of Gag-specific cytotoxic responses were also associated with a lower viral load in some analyses (Table 2 in our article), which, together with Env-specific responses, justifies our conclusion that the induction of memory cytotoxic T lymphocytes contributes to the control of viral replication.

The relation between the frequency of precursor cytotoxic T lymphocytes recognizing HIV-1 Env and the decline in CD4+ counts to a level of less than 300 per cubic millimeter, when adjusted for the initial CD4+ count, does not change (unadjusted relative risk, 0.18; adjusted relative risk, 0.22), although the standard error increases (95 percent confidence intervals: unadjusted, 0.03 to 0.98; adjusted, 0.04 to 1.39). The levels of Gag-specific or Pol-specific precursor frequencies have virtually no predictive value in determining declines in CD4+ counts to a level of less than 300 per cubic millimeter (relative risk adjusted for CD4+ counts: Gag, 0.74 [P = 0.69]; Pol, 1.03 [P = 0.97]). Thus, we again conclude that Env-specific responses may contribute to the delay in the progression of HIV-1 disease.

M. Juliana McElrath, M.D., Ph.D.
Fred Hutchinson Cancer Research Center, Seattle, WA 98104

James Hughes, Ph.D.
Luwy Musey, M.D.
University of Washington, Seattle, WA 98105

1 References