SummaryCytotoxicity mediated by natural killer (NK) and lymphokine-activated killer (LAK) cells may be of significance in host defense against viral infections. This study included 347 patients infected with human immunodeficiency syndrome virus (HIV) type 1 and 110 controls. The NK cell activity, either unstimulated or stimulated with interferon-tx (IFN-tx) or interleukin-2 (IL2), and the LAK cell activity were suppressed in patients, but the NK/LAK cell activity did not differ between patients with AIDS and patients without AIDS. However, the IFN-ol-stimulated NK cell activity and LAK cell activity were reduced in patients with symptoms of HIV disease (CDCIV) when compared with asymptomatic patients (CDCII + III). When the data were analyzed by multiple linear regression, the percentage of CD4 + cells had a positive effect on these two parameters in patients without AIDS, whereas the percentage of CD4 + cells had no significant effect on unstimulated and IL-2-stimulated NK cell activity in these patients. In controis and AIDS patients, the percentage of CD4 + cells had no effect on NK/LAK cell activity in multiple linear models. The total number of CD16 § cells was low in patients compared to controls, whereas the percentages of CD16 +, CD56 +, and CD16 + CD56 + were either normal or elevated. Therefore, the decrease in NK cell subpopulations did not contribute to the observed depression in NK/LAK cell activity in vitro. It is concluded that natural immunity is suppressed in HIV-seropositive patients primarily because of a qualitative defect of the NK/LAK cells. This qualitative defect includes a reduced responsiveness to IFN-c~, which is progressive until the onset of symptoms, and possibly related to the loss of CD4 + cells.

Macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES production were measured by ELISA in whole blood that had been stimulated for 4.5 h with phytohemagglutinin. The blood was from 90 healthy human immunodeficiency virus (HIV)-negative controls and from 245 HIV-infected subjects who were followed for< or = 4.5 years. HIV-infected persons without AIDS had increased levels of MIP-1alpha, MIP-1beta, and RANTES (P < .01) compared with levels in controls. Subjects with AIDS, compared with controls, had decreased production levels of MIP-1beta (P < .0001) and similar levels of MIP-1alpha and RANTES. A high level of MIP-1beta production was associated with a decreased risk of progressing to AIDS or death, as determined by univariate analysis (P < .01) and adjusted for CD4 cell count and age (P = .07, P = .06, respectively). The findings suggest that the production level of beta-chemokine changes during HIV infection and that a high level of beta-chemokine production in peripheral blood lymphocytes may be associated with less rapid disease progression in HIV infection.

Trygfonden, Lundbeckfonden, and the Danish National Research Foundation.

This study confirms a selective loss of memory CD4+ cells early in HIV infection followed by increased loss of naive CD4+ cells in later stages of the infection. The loss of naive CD4+ cells seems to be important in the pathogenesis of terminal HIV infection.

The present study suggests that low LAK cell activity and low NK cell responsiveness to interferon-alpha may be important in the pathogenesis of HIV infection.