A novel mechanism of CD4 lymphocyte depletion involves effects of HIV on resting lymphocytes: Induction of lymph node homing and apoptosis upon secondary signaling through homing receptors

Recently, we reported that abortive HIV infection of resting human T lympho cytes up-regulated expression of CD62L, the receptor for homing to lymph no des (LNs), and enhanced homing of these cells from the blood into the LNs ( Wang et al,, 1997, Virology 228:141), This suggested that HIV-induced homin g of resting lymphocytes (which comprise >98% of all lymphocytes) may be a major mechanism for the reduction of CD4(+) lymphocytes in the blood of inf ected individuals. This mechanism also could be partially responsible for t he lymphadenopathy that often develops at the same time that CD4(+) lymphoc ytes are disappearing from the blood. In this study, we show that secondary signaling through the homing receptors (CD62L, CD44, CD11a) of abortively infected resting CD4(+) T lymphocytes induced apoptosis, These signals woul d occur as the cells home into the LNs. Apoptosis did not occur after secon dary signaling through some other receptors (CD26, CD4, CD45, and HLA class I) or in HIV-exposed resting CD8(+) lymphocytes signaled through the homin g receptors, These findings indicate that HIV-induced homing of resting CD4 (+) lymphocytes to LNs results in death of many of these cells. This was co nfirmed in the LNs of SCID mice that were i.v. injected with HIV-exposed re sting human lymphocytes, Thus, these effects of HIV upon binding to resting CD4(+) T lymphocytes, which are not permissive for HIV replication, may si gnificantly contribute to their depletion in vivo. These findings also offe r an explanation for the bystander effect observed in the LNs of AIDS patie nts, whereby cells not making virus are dying.