Immune Failure in the Absence of Profound CD4⁺T-Lymphocyte Depletion in Simian Immunodeficiency Virus-Infected Rapid Progressor Macaques

Abstract

A fraction of simian immunodeficiency virus (SIV)-infected macaques develop rapidly progressive disease in the apparent absence of detectable SIV-specific antibody responses. To characterize the immunopathogenesis of this syndrome, we studied viral load, CD4؉ T-lymphocyte numbers as well as cellular and humoral immune responses to SIV and other exogenous antigens in four SIVsm-infected rhesus macaques that progressed to AIDS 9 to 16 weeks postinoculation. Each of these animals exhibited high levels of viremia but showed relatively preserved CD4 T lymphocytes in blood and lymphoid tissues at the time of death. Transient SIV-specific antibody responses and cytotoxic T-lymphocyte responses were observed at 2 to 4 weeks postinoculation. Two of the macaques that were immunized sequentially with tetanus toxoid and hepatitis A virus failed to develop antibody to either antigen. These studies show that the SIV-infected rapid progressor macaques initially mounted an appropriate but transient cellular and humoral immune response. The subsequent immune defect in these animals appeared to be global, affecting both cellular and humoral immunity to SIV as well as immune responses against unrelated antigens. The lack of CD4 depletion and loss of humoral and cellular immune responses suggest that their immune defect may be due to an early loss in T helper function.

IL-15 Treatment during Acute Simian Immunodeficiency Virus (SIV) Infection Increases Viral Set Point and Accelerates Disease Progression despite the Induction of Stronger SIV-Specific CD8+ T Cell Responses

“…More studies are necessary to examine more carefully the effect of IL-15 on B cell function. The decreased anti-SIV Abs could indeed influence the outcome of SIV infection, as it was shown before that during progression to HIV and SIV, Abs specific for HIV and SIV decrease or are absent (65,66). We observed an inverse correlation between the amount of anti-SIV Abs and viral replication at week 16.…”

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

“…For HIV-1, CXCR4-utilizing strains, which target and rapidly eliminate both naïve and memory CD4 ϩ T cells, are frequently recovered from human rapid progressors (24, 30), in contrast to R5-tropic viral isolates, which replicate exclusively in CD4 memory cells and are the predominant strains detected in the majority of patients experiencing a "normal" disease course (6,46). Another feature of the SIV RP syndrome rarely observed in HIV-1-infected individuals is the systemic and unrestricted infection of tissue macrophages that sustains high levels of viremia in infected macaques following the destruction and elimination of the memory CD4 ϩ T-lymphocyte population (16). The latter is reminiscent of macaques infected with highly pathogenic SHIVs in which virus production is also maintained by tissue macrophages following the rapid and irreversible depletion of CD4 ϩ T-cell targets (20).…”

“…Such rapid progressors (RPs) experience persistently high levels of plasma viremia/p27 antigenemia, undetectable or transient anti-SIV antibody responses that wane within 3 to 4 weeks of virus inoculation, and the early onset of clinical disease characterized by marked weight loss, chronic diarrhea, and cachexia (16,37). SIV preferentially targets the elimination of the memory CD4 ϩ T-cell subset residing in effector sites during the primary infection, since these lymphocytes express the highest levels of CCR5 (10).…”

Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques

“…36 CD4 þ T-cell counts turned out to be an inadequate marker for the diagnosis of AIDS since many rapid progressors still had increasing CD4 þ counts by the time of euthanasia. 36,51,52 Viral RNA copy number could not be used as a proxy for AIDS as many monkeys were infected at a time when RNA copy number was not routinely analyzed. However, for most monkeys cellassociated viral load data were available.…”