Insufficient Production and Tissue Delivery of CD4+Memory T Cells in Rapidly Progressive Simian Immunodeficiency Virus Infection

Abstract

The mechanisms linking human immunodeficiency virus replication to the progressive immunodeficiency of acquired immune deficiency syndrome are controversial, particularly the relative contribution of CD4+ T cell destruction. Here, we used the simian immunodeficiency virus (SIV) model to investigate the relationship between systemic CD4+ T cell dynamics and rapid disease progression. Of 18 rhesus macaques (RMs) infected with CCR5-tropic SIVmac239 (n = 14) or CXCR4-tropic SIVmac155T3 (n = 4), 4 of the former group manifested end-stage SIV disease by 200 d after infection. In SIVmac155T3 infections, naive CD4+ T cells were dramatically depleted, but this population was spared by SIVmac239, even in rapid progressors. In contrast, all SIVmac239-infected RMs demonstrated substantial systemic depletion of CD4+ memory T cells by day 28 after infection. Surprisingly, the extent of CD4+ memory T cell depletion was not, by itself, a strong predictor of rapid progression. However, in all RMs destined for stable infection, this depletion was countered by a striking increase in production of short-lived CD4+ memory T cells, many of which rapidly migrated to tissue. In all rapid progressors (P < 0.0001), production of these cells initiated but failed by day 42 of infection, and tissue delivery of new CD4+ memory T cells ceased. Thus, although profound depletion of tissue CD4+ memory T cells appeared to be a prerequisite for early pathogenesis, it was the inability to respond to this depletion with sustained production of tissue-homing CD4+ memory T cells that best distinguished rapid progressors, suggesting that mechanisms of the CD4+ memory T cell generation play a crucial role in maintaining immune homeostasis in stable SIV infection.

Apoptosis in SIV infection

“…[175][176][177] Moreover, CD4 þ T cells expressing CCR5 decreases at the peak of viral replication in both pathogenic and nonpathogenic SIV-infected monkeys. 166,[178][179][180] Altogether, these observations may indicate that depletion of CCR5 þ CD4 þ T cells is an important event but likely is not the only factor involved in AIDS pathogenesis. These observations also raise questions about the role of alternative chemokine receptors in the immunopathogenesis of AIDS.…”

Do most lymphocytes in humans really reside in the gut?

“…During the chronic phase of HIV or SIV infection, a homeostatic response attempts to compensate for the ongoing depletion of CD4 + T cells in the gut [22]. If the gut indeed contains the majority of CD4 + T cells, it is easy to imagine that the magnitude of the homeostatic response would be too large to be sustained over long periods of time [23].…”

A mechanistic model for bromodeoxyuridine dilution naturally explains labelling data of self-renewing T cell populations

“…BrdU has been used for decades in mice [11,12], and more recently in monkeys [13][14][15]. Because of potential problems with toxicity, it has been used infrequently in humans [16][17][18][19][20], and only over short-term periods.…”