Loss of Naïve Cells Accompanies Memory CD4 ⁺ T-Cell Depletion during Long-Term Progression to AIDS in Simian Immunodeficiency Virus-Infected Macaques

Abstract

Human immunodeficiency virus and simian immunodeficiency virus (SIV) induce a slow progressive disease, characterized by the massive loss of memory CD4؉ T cells during the acute infection followed by a recovery phase in which virus replication is partially controlled. However, because the initial injury is so severe and virus production persists, the immune system eventually collapses and a symptomatic fatal disease invariably occurs. We have assessed CD4؉ T-cell dynamics and disease progression in 12 SIV-infected rhesus monkeys for nearly 2 years. Three macaques exhibiting a rapid progressor phenotype experienced rapid and irreversible loss of memory, but not naïve, CD4؉ T lymphocytes from peripheral blood and secondary lymphoid tissues and died within the first 6 months of virus inoculation. In contrast, SIV-infected conventional progressor animals sustained marked but incomplete depletions of memory CD4 ؉ T cells and continuous activation/proliferation of this T-lymphocyte subset. This was associated with a profound loss of naïve CD4 ؉ T cells from peripheral blood and secondary lymphoid tissues, which declined at rates that correlated with disease progression. These data suggest that the persistent loss of memory CD4 ؉ T cells, which are being eliminated by direct virus killing and activation-induced cell death, requires the continuous differentiation of naïve into memory CD4 ؉ T cells. This unrelenting replenishment process eventually leads to the exhaustion of the naïve CD4 ؉ T-cell pool and the development of disease.

Generation of the Pathogenic R5-Tropic Simian/Human Immunodeficiency Virus SHIV AD8 by Serial Passaging in Rhesus Macaques

“…and a plasma viral load of only 5.4 ϫ 10 2 RNA copies/ml. During the chronic phase of SHIV AD8 infections, the loss of naïve CD4 ϩ T cells was more rapid and more marked than the depletion of the memory subset, as was previously observed in SIVsmE543-infected animals (35) (Fig. 6).…”

“…of symptomatic disease (6). Despite losing virtually all of their memory CD4 ϩ T lymphocytes, SIV RPs, at the time of death, usually maintain preinoculation levels of naïve CD4 ϩ T cells (35). This was not the case for SHIV AD8 RPs.…”

“…(35). It was therefore not unexpected that NP SHIV AD8 -infected monkeys might also sustain a depletion of their naïve CD4 ϩ T cell subset.…”

Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate

“…However, three of the monkeys infected with SIVsmE660 (CP3C, CG7G, and AK9F) had undetectable plasma viral RNA levels by 700 days postinfection, while monkey CR54 had an undetectable plasma viral RNA levels by 85 days postinfection. This wide range in peak and set point viremias in monkeys infected with SIVsmE660 has been previously described (7,19,35). Since plasma viral RNA levels at peak and set point in some of the SIVsmE660-infected monkeys (CP37, CP23, and CG7G) were of a magnitude comparable to that seen in monkeys following SIVmac251 infection, the variability in SIVsmE660 replication levels in monkeys likely reflects a host factor effect rather than an intrinsic lack of replicative capacity of the SIVsmE660 strain.…”

Most rhesus macaques infected with the CCR5-tropic SHIV AD8 generate cross-reactive antibodies that neutralize multiple HIV-1 strains

“…EDTA-treated blood samples and BAL fluid lymphocytes were stained for flow cytometric analysis as described previously (30)(31)(32).…”