Background:  HIV infection leads to a state of chronic immune activation and progressive deterioration in immune function, manifested most recognizably by the progressive depletion of CD4⁺ T cells. A substantial percentage of natural killer (NK) cells from patients with HIV infection are activated and express the natural cytotoxicity receptor (NCR) NKp44.

Methods:  Blood samples were collected from 20 HIV^– individuals and >100 HIV⁺ patients at different stages of HIV infection. Cell surface expression of NKp44L was analyzed using flow cytometric analysis, the engagement of NKp44L during the NK lysis process was evaluated using a standard ⁵¹Cr release assay, and the level of anti-3S antibodies production was detected by ELISA in the serum samples.

Results:  We showed that a cellular ligand for the NCR NKp44 (NKp44L) is expressed during HIV-1 infection and is correlated with both the progression of CD4⁺ T cell depletion and the increase of viral load. CD4⁺ T cells expressing this NKp44L ligand are highly sensitive to the NK lysis activity mediated by NKp44⁺ NK cells. The ligand’s expression is strongly induced by the linear motif NH2-SWSNKS-COOH of the HIV-1 envelope gp41 protein, called 3S. This highly conserved 3S motif appears critical to the sharp increase in NK lysis of CD4⁺ T cells from HIV-infected patients. Furthermore, to assess the possibility that anti-3S antibodies might protect CD4⁺ T cells from NK lysis, we examined the occurrence and function of these antibodies in HIV-infected patients and showed that the production of anti-3S antibodies was observed in around 30% of HIV-infected patients and was inversely correlated with both the CD4 cells count and NKp44L expression on CD4⁺ T cells, particularly, in slow progressor patients.

Conclusions:  This study may provide one of the first demonstrations that specific B and T helper memory immune responses can influence NK cytotoxicity directed against autologous CD4⁺ T cells. In addition, this study may have important implications for therapeutic vaccines against AIDS directed not against the pathogen, but against the pathogenesis.