Lymphocyte Activation during Acute Simian/Human Immunodeficiency Virus SHIV_89.6PDInfection in Macaques

Abstract

Host-virus interactions control disease progression in human immunodeficiency virus-infected human beings and in nonhuman primates infected with simian or simian/human immunodeficiency viruses (SHIV). These interactions evolve rapidly during acute infection and are key to the mechanisms of viral persistence and AIDS. SHIV89.6PDinfection in rhesus macaques can deplete CD4+ T cells from the peripheral blood, spleen, and lymph nodes within 2 weeks after exposure and is a model for virulent, acute infection. Lymphocytes isolated from blood and tissues during the interval of acute SHIV89.6PD infection have lost the capacity to proliferate in response to phytohemagglutinin (PHA). T-cell unresponsiveness to mitogen occurred within 1 week after mucosal inoculation yet prior to massive CD4+ T-cell depletion and extensive virus dissemination. The lack of mitogen response was due to apoptosis in vitro, and increased activation marker expression on circulating T cells in vivo coincided with the appearance of PHA-induced apoptosis in vitro. Inappropriately high immune stimulation associated with rapid loss of mature CD4+ T cells suggested that activation-induced cell death is a mechanism for helper T-cell depletion in the brief period before widespread virus dissemination. Elevated levels of lymphocyte activation likely enhance SHIV89.6PD replication, thus increasing the loss of CD4+ T cells and diminishing the levels of virus-specific immunity that remain after acute infection. The level of surviving immunity may dictate the capacity to control virus replication and disease progression. We describe this level of immune competence as the host set point to show its pivotal role in AIDS pathogenesis.

Role of the Fas/FasL Pathway in HIV or SIV Disease

“…The acute stage has high levels of FasL mRNA expression that diminishes during the chronic stage. This observation coincides with earlier published studies showing a high level of PBMC-susceptibility to AICD during the acute stage of SIV infection, and this susceptibility subsides during the chronic stage [ 58 ].…”

T-cell response relative to genotype and ethnicity during antiviral therapy for chronic hepatitis C

“…Although unresponsiveness to PHA may be associated with the frequency and activation of the circulating T cells ( e.g. , in simian/human immunodeficiency virus),41 there was no significant difference in circulating total T‐cell or regulatory CD4 + CD25 + T‐cell frequencies in our patient subgroups. PHA response also can be a function of accessory cells such as monocytes and dendritic cells as well as their secreted factors ( e.g.…”

Mucosal arenavirus infection of primates can protect them from lethal hemorrhagic fever

“…Proliferative responses to LCMV antigen were observed in all three challenge-surviving monkeys but not in monkeys that succumbed to lethal challenge. It was curious that proliferative capacity frequently decreased following inoculation with more virus; so we tested the hypothesis that decreases in SI were due to AICD as observed in AIDS [Wallace et al, 1999]. This was not the case, however, since lymphocyte subsets were just as susceptible to cell death before and after activation with PHA ( Fig.…”

“…6). PBMC were incubated with or without 1 mg/ ml of PHA, and then were stained with 7-AAD as an early marker for apoptosis [Wallace et al, 1999]. In general, early PBMC samples had higher dramatic increases in cell death as a result of PHA activation (Fig.…”

“…5). There are at least two explanations for this drop in proliferative capacity after an antigenic boost: (1) T H cells were being depleted from the circulation by being sequestered to virus-infected tissues, and (2) viral antigens made lymphocytes susceptible to AICD as seen in AIDS [Wallace et al, 1999]. To explore this latter possibility for Rh-ig8 (ARM) and Rh-iv3 (ARM) we performed a flow cytometric analysis of different lymphocyte subsets after activation with PHA ( Fig.…”