Immune and hematopoietic parameters in HIV‐1‐infected chimpanzees during clinical progression toward AIDS

Abstract

Until recently, chimpanzees were considered susceptible to human immunodeficiency virus type 1 (HIV-1) infection, but refractory to disease induction based on the asymptomatic status of all experimentally infected chimpanzees after over 10 years postinfection (PI). However, a decline in peripheral CD4+ T cells was noted in one chimpanzee (C499) of the Yerkes cohort of HIV-1 infected apes, after 11 years PI concurrent with increasing plasma viral load. These clinical signs were followed by the occurrence of opportunistic infections, thrombocytopenia, and progressive anemia leading to euthanasia. A second chimpanzee (C455) was transfused with blood from C499 collected during the symptomatic stage. Shortly thereafter, this second animal showed a rapid decline in peripheral CD4+ T-cell levels and sustained high viral load. Hematological analyses showed a 50% decrease in CFU-GM for both apes during the symptomatic phase and a reduction of 40% and 73% of the total CFU despite normal levels of CD34+ cells in the bone marrow. Cryopreserved sequential PBMC samples from these two chimpanzees were analyzed for constitutive and PHA-P induced levels of cytokines and chemokines. Data show that whereas there were no detectable constitutive levels of mRNA coding for IL-2, 4, and 10, there appears to be a transient increase in IFN-gamma message level coincident with increased viremia and this IFN-gamma synthesis decreased with disease progression. PHA-induced cytokine mRNA analysis showed low or undetectable levels of IL-4 and IL-10 mRNA in all samples and a marked decrease in the levels of IL-2 shortly after HIV infection. In addition, there was also a gradual decrease in IFN-gamma mRNA with progression of disease. Of interest were the findings of high to normal levels of PHA-induced synthesis of the chemokines MIP-1alpha, MIP-1beta, and RANTES in samples during the asymptomatic and early symptomatic period, which also dramatically decreased at late stages of the disease. These data suggest important roles for IL-2, IFN-gamma, and the chemokines in the regulation of immune responses in HIV-1-infected chimpanzees.

Human and Simian Immunodeficiency Virus-Mediated Upregulation of the Apoptotic Factor TRAIL Occurs in Antigen-Presenting Cells from AIDS-Susceptible but Not from AIDS-Resistant Species

“…Additional evidence suggests that apoptosis occurs significantly less in species such as chimpanzees and SM that do not develop AIDS (10,17,49). In the rare cases when chimpanzees do progress to AIDS, the loss of CD4 ϩ T cells and increased apoptosis have been observed previously (9,48).…”

Human retroviruses and AIDS 1997

“…They can be infected with HTV, but progress to AIDS very slowly after HTV infection. Thus far, only one chimpanzee has died from an AIDS-like illness, ten years after infection with HIV-1 (Villinger et al, 1997). This is a drawback in the light of recent discussions about the lack of necessity for sterilizing immunity (the total prevention of infection, as opposed to partial immunity, where infection after vaccination can occur but is less severe).…”

A Single Amino Acid Difference between Human and Monkey Interleukin (IL)-1β Dictates Effective Binding to Soluble Type II IL-1 Receptor

“…A comparative study of multiple cytokine sequences in nonhuman primates noted that the level of sequence conservation with human orthologs varied considerably (21). Despite the high degree of sequence homology, IL-1␣ and IL-1␤ were among the most diverged cytokines between human and monkey.…”

“…Sequences for both of these Old World monkey IL-1␤ cDNAs were previously published (20,21) and were available from GenBank TM (accession numbers D63353 and MMU19845). The cynomolgus IL-1␤ cDNA was obtained from activated PBMCs and was found to have two nucleotide substitutions relative to the publicly available cynomolgus sequence (accession number D63353).…”