Distinct Cycling CD4⁺- and CD8⁺-T-Cell Profiles during the Asymptomatic Phase of Simian Immunodeficiency Virus SIVmac251 Infection in Rhesus Macaques

Abstract

Elevated CD4 T-cell turnover may lead to the exhaustion of the immune system during human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) infections. However, this hypothesis remains controversial. Most studies of this subject have concerned the blood, and information about the lymph nodes is rare and controversial. We used Ki67 expression to measure cycling T cells in the blood and lymph nodes of uninfected macaques and of macaques infected with a pathogenic SIVmac251 strain or with a nonpathogenic SIVmac251⌬nef clone. During the asymptomatic phase of infection, the number of cycling CD8 ؉ T cells progressively increased (two-to eightfold) both in the blood and in the lymph nodes of macaques infected with SIVmac251. This increase was correlated with viral replication and the progression to AIDS. In contrast, no increases in the numbers of cycling CD4؉ T cells were found in the blood or lymph nodes of macaques infected with the pathogenic SIVmac251 strain in comparison with SIVmac251⌬nef-infected or healthy macaques during this chronic phase. However, the lymph nodes of pre-AIDS stage SIVmac251-infected macaques contained more cycling CD4 ؉ T cells (low baseline CD4 ؉ -T-cell counts in the blood). Taken together, these results show that the profiles of CD4؉ -and CD8 ؉ -T-cell dynamics are distinct both in the lymph nodes and blood and suggest that higher CD4؉ -T-cell proliferation at the onset of AIDS may lead to the exhaustion of the immune system. Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replicate continuously, with the rapid turnover of virions and the productive infection of CD4ϩ lymphocytes (37, 45). As infection progresses, the CD4 ϩ -T-cell count in the blood progressively declines, and in AIDS stage patients, opportunistic infections supervene, eventually resulting in death (44). The rate of progression to AIDS and death is correlated with the amount of viral RNA and the number of circulating CD4 ϩ T cells in the blood. Despite intensive investigations, the reason for the depletion of CD4 ϩ

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

“…38 While we clearly found a positive correlation between the extent of viral replication in peripheral lymphoid tissues (e.g. Figure 4d) and the rate of cycling cells in LNs, consistent with previous findings, 13,14 our data revealed a markedly distinct picture in Mes LNs. Thus, the positive relationship in peripheral LNs might be a consequence of the relapse of SIV from reservoir sites and reflects active antiviral defenses and likely protective responses.…”

CD8+ T Cell Dynamics during Primary Simian Immunodeficiency Virus Infection in Macaques: Relationship of Effector Cell Differentiation with the Extent of Viral Replication

“…The concentration of these Abs increased thereafter (data not shown). According to our recent results (23,42), none of this new group of infected primates were rapid progressors, i.e., they did not develop AIDS (wasting syndrome with cachexia, opportunistic infections, and an absence of SIV Ab response) within 6 mo. To determine the extent of the early viral seeding in peripheral lymphoid organs, we also analyzed peripheral LNs.…”

“…94746, 94852, 94856, R97087, 94860; mean: 1.2 ϫ 10 5 SIV RNA copies/ml, range: 2 ϫ 10 4 to 3.4 ϫ 10 5 ; p ϭ 0.009). These set points are predictive of further progression to AIDS, identifying slow and moderate progressors, respectively (23,42). Three animals (nos.…”

“…Infected cells, detected as spots, were counted in the paracortical zone on a minimum of three sections using a Nikon-FXA microscope. The numbers of LN-positive cells (spots) counted were then divided by the surface of the entire LN section, and results were expressed as positive cell numbers/2 mm 2 section as previously described (17,23,42). The mean count obtained for three slides is indicated.…”

Sanctuaire du virus de l’immunodéficience humaine et mécanismes d’échappement

“…Celle-ci pourrait résulter, au moins en partie, d'une activation chronique de ces cellules (AICD, activationinduced cell death). Cette hypothèse se fondait sur l'observation que, dans le sang, il existe une corrélation entre le pourcentage de lymphocytes T CD8 circulants activés -exprimant des marqueurs d'activation ou d'entrée en cycle comme la molécule Ki67 -et la réplication virale, et la rapidité d'évolution de la maladie chez l'homme comme chez le macaque [8,[16][17][18]. Nos analyses chez le macaque montrent qu'en fait les lymphocytes T CD8 isolés des ganglions mésentériques expriment très peu la molécule Ki67, contrairement aux lymphocytes T CD8 isolés des ganglions périphériques et du sang, suggérant l'existence d'autres mécanismes que l'AICD.…”