Decreased Levels of Recent Thymic Emigrants in Peripheral Blood of Simian Immunodeficiency Virus-Infected Macaques Correlate with Alterations within the Thymus

Abstract

The thymus is responsible for de novo production of CD4؉ and CD8 ؉ T cells and therefore is essential for T-cell renewal. The goal of this study was to assess the impact of simian immunodeficiency virus (SIV) infection on the production of T cells by the thymus. Levels of recent thymic emigrants within the peripheral blood were assessed through quantification of macaque T-cell receptor excision circles (TREC). Comparison of SIVinfected macaques (n ‫؍‬ 15) to uninfected macaques (n ‫؍‬ 23) revealed stable or increased TREC levels at 20 to 34 weeks postinfection. Further assessment of SIV-infected macaques (n ‫؍‬ 4) determined that TREC levels decreased between 24 and 48 weeks postinfection. Through the assessment of longitudinal time points in three additional SIVmac239-infected macaques, the SIV infection was divided into two distinct phases. During phase 1 (16 to 30 weeks), TREC levels remained stable or increased within both the CD4 and CD8 T-cell populations. During phase 2 (after 16 to 30 weeks), TREC levels declined in both T-cell populations. As has been described for human immunodeficiency virus (HIV)-infected patients, this decline in TREC levels did at times correlate with an increased level of T-cell proliferation (Ki67؉ cells). However, not all TREC decreases could be attributed to increased T-cell proliferation. Further evidence for thymic dysfunction was observed directly in a SIVmac239-infected macaque that succumbed to simian AIDS at 65 weeks postinfection. The thymus of this macaque contained an increased number of memory/effector CD8 ؉ T cells and an increased level of apoptotic cells. In summary, reduced levels of TREC can be observed beginning at 16 to 30 weeks post-SIV infection and correlate with changes indicative of dysfunction within the thymic tissue. SIV infection of macaques will be a useful model system to elucidate the mechanisms responsible for the thymic dysfunction observed in HIVinfected patients.

Apoptosis in SIV infection

“…76 The fact that apoptosis in the thymus as well as in the LNs of macaques infected with pathogenic SIV occurs in both infected and uninfected T cells indicates again that mechanisms other than the direct cytopathic effect of HIV are involved in this disease process. 53,77 Furthermore, studies performed in pathogenic and nonpathogenic primate models of HIV or SIV infection during the chronic asymptomatic phase have identified a correlation between the induction of enhanced in vitro T-cell apoptosis and the in vivo pathogenic nature of the retroviral infection 27,44,51,78-84 ( Figure 1b). Thus, enhanced levels of apoptosis in CD4 þ T cells were observed in HIV-1-infected human individuals, rhesus macaques infected with a pathogenic strain of SIVmac, and chimpanzees infected with a pathogenic strain of SIVcpz leading to AIDS, 78,85 while enhanced CD8 T-cell apoptosis was observed in both pathogenic and nonpathogenic primate models.…”

Effacing of the T Cell Compartment by Cardiac Transplantation in Infancy

“…TREC consist of fragments of DNA excised during rearrangement of TCR genes and hence TREC levels represent the function of the thymus. Thus, aged subjects with an atrophied thymus have a 20-fold decrease in levels of TREC compared with young subjects (22) and nonhuman primates subjected to thymectomy have a 40-fold decrease in the levels of TREC 1 year after the procedure (23,24). If the T cell compartment of recipients of cardiac transplants was restored by proliferation of residual T cells, a decrease in levels of TREC in these subjects would indicate a lack of thymic function.…”

Fusion-Induced Apoptosis Contributes to Thymocyte Depletion by a Pathogenic Human Immunodeficiency Virus Type 1 Envelope in the Human Thymus

“…Furthermore, recovery of thymic function after highly active antiretroviral therapy has been correlated with immune recovery (15)(16)(17)36). Thymic sections from HIV-1-infected humans or SIV/SHIV-infected macaques show increased apoptosis, suggesting that HIV-1 can either directly or indirectly hasten thymocyte depletion (28,29,45,47,56). A number of studies addressing mechanisms of CD4 ϩ thymocyte death in the thymus organ have indicated that both direct viral lysis and bystander apoptosis occur during thymocyte depletion (5,6,30,48).…”