MODULATION OF ANTIGEN-SPECIFIC IMMUNE RESPONSES IN SIV-INFECTED PIGTAIL MACAQUES

Abstract

Depletion of the CD4+ cell subset in retroviral infections causes impaired immunological function in primates and eventually complete erosion of immune defense. Evidence from in vitro and in situ studies has linked HIV and SIV to programmed cell death in activated T cells. This study proposes an in vivo demonstration of antigen specific T cell depletion. The theoretical mechanism of this action is based on the 2 signal model. Cellular MI-IC antigens and viral envelope gp120 activate T cell targets inappropriately such that subsequent interaction with antigen presenting cells triggers apoptosis in the T cell. This experiment is designed to drive clonal deletion of Tetanus toxoid-specific T cells in macaques previously immunized with Tetanus and Diphtheria toxoids. Two macaques out of six received excess Tetanus toxoid at the time of peak viremia following SIV infection. Two control animals received Tetanus, but were not infected; and two animals were infected without Tetanus immune stimulation. A limiting dilution assay was developed to determine Tetanus-specific cell numbers. Tetanus -specific T cells in peripheral blood were initially suppressed or deleted by viral infection. The infected animals recovered Tetanus titers upon clearance of primary viremia and in response to Tetanus immune stimulation. Clonal deletion of the Tetanus precursor population was not observed as a result of excess antigen during primary SIV viremia. The infected macaques did experience a loss of type 1 recall response to Tetanus 6 months following infection. This is consistent with observations of HIV-infected humans. The loss of recall was not specific to Tetanus; the Diphtheria response was also eroded. Two of the four infected animals died prematurely at 3 and 7 months post-infection. Neither animal generated an antibody response to capsid protein. This phenomenon is a characteristic of fast-progressors in humans infected with HIV. The SIV infection of primates remains a good experimental model for HIV infection in humans. Pigtail macaques are quite similar in infection parameters and immunological responses. In terms of responsiveness to Tetanus/Diphtheria toxoids, macaques have a less intense and shorter duration of memory response. This should be considered when designing experiments involving common recall antigens in the nonhuman primate model.