HIV infection leads to a gradual deterioration in immune status. The mechanisms underlying CD4 T cell depletion in this setting are controversial. One of the most intriguing phenomena is that many uninfected CD4 cells die prematurely in HIV-infected subjects. We therefore investigated the possibility that these cells are killed by a collateral effector mechanism. Here we show that a cellular ligand for the natural cytotoxicity receptor NKp44 (NKp44L) is expressed during HIV infection, and that its expression correlates both with CD4 T cell depletion and with an increase in viral load. CD4+ T cells expressing the NKp44L ligand are highly sensitive to the lytic activity of NKp44+ NK cells. NKp44L ligand expression is strongly induced by the highly conserved 3S motif of the HIV-1 envelope protein gp41. Anti-3S antibodies, detected early in the disease, protect CD4+ T cells from NK-mediated lysis during incubation with 3S. In addition, anti-3S antibody titers correlate positively with CD4+ T cell numbers and negatively with NKp44L expression on CD4 T cells. To determine whether anti-3S immunization might prevent NKp44L expression on CD4 T cells in vivo and thereby prevent the decline in CD4 T cells, macaques were immunized with 3S and then infected with the simian virus SHIV162P3. 3S peptide vaccination elicited antibodies that prevented CD4+ T cell depletion (percentage and absolute number), and also NK activation and cytotoxicity, without halting virus replication. These data raise new questions on HIV infection and point to novel preventive and therapeutic vaccine strategies.