This project is directed at delineating the pathogenic mechanisms of HIV infection and the role of immune activation in the propagation of disease and destruction of the immune system. We studied the effect of immunization with a common recall antigen on viral expression and the ability to isolate virus from peripheral blood lymphocytes (PBMCs) in 13 HIV-1 infected patients. We also examined the susceptibility to in vitro HIV-1 infection of PBMCs from control subjects not infected with HIV-1 before and after tetanus immunization. We demonstrated that, after tetanus toxoid booster inoculation, all 13 HIV-1 infected patients had transient increases in plasma viremia; increases in proviral burden ocurred in 11/13. Lymph node tissue obtained before and after immunization from two infected individuals revealed increased proviral burden and viral RNA after immunization in both patients. HIV was more easily isolated from PBMCs obtained after immunization from the majority of patients compared to PBMCs obtained before immunization. We also demonstrated an enhanced ability to culture virus from PBMCs of immunized HIV-1 infected patients when the immunizing antigen (tetanus) was added to the cultures, even in the absence of additional mitogens. PBMCs obtained after immunization of uninfected volunteers were often more susceptible to in vitro HIV infection compared to the susceptibility of PBMCs obtained prior to immunization. Preliminary examination of HIV-1 quasi-species in three patients revealed that in vivo activation from immunizations expands pre-existing plasma viruses that were predominating in the plasma at the time of immunization. Long-lived latently-infected cells do not appear to significantly contribute to the induced virus with the probable exception of those individuals with more advanced disease. Immunization favored the expansion of M-tropic (NSI) over dual tropic (SI) viruses in one individual. In another patient, immunization was associated with an initial expansion and then clearance of major virus groups from the plasma. Immune activation in vivo is associated with a down regulation of CXCR4 expression and up-regulation of CCR5 expression on PBMCs in both HIV-1 infected and uninfected individuals.
