Production of β‐Chemokines in Human Immunodeficiency Virus (HIV) Infection: Evidence that High Levels of Macrophage Inflammatory Protein‐1β Are Associated with a Decreased Risk of HIV Disease Progression

Abstract

Macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES production were measured by ELISA in whole blood that had been stimulated for 4.5 h with phytohemagglutinin. The blood was from 90 healthy human immunodeficiency virus (HIV)-negative controls and from 245 HIV-infected subjects who were followed for< or = 4.5 years. HIV-infected persons without AIDS had increased levels of MIP-1alpha, MIP-1beta, and RANTES (P < .01) compared with levels in controls. Subjects with AIDS, compared with controls, had decreased production levels of MIP-1beta (P < .0001) and similar levels of MIP-1alpha and RANTES. A high level of MIP-1beta production was associated with a decreased risk of progressing to AIDS or death, as determined by univariate analysis (P < .01) and adjusted for CD4 cell count and age (P = .07, P = .06, respectively). The findings suggest that the production level of beta-chemokine changes during HIV infection and that a high level of beta-chemokine production in peripheral blood lymphocytes may be associated with less rapid disease progression in HIV infection.

Spontaneous and antigen-induced production of HIV-inhibitory β-chemokines are associated with AIDS-free status

“…Other studies performed by analyzing plasma͞serum levels of ␤-chemokines that did not show a positive effect of chemokines in HIV infection (50)(51)(52)(53)(54)(55)(56) probably were affected by this unspecific release. Similar to the results of Ullum et al (33), we have found a more significant role of MIP-1␣ and MIP-1␤ in disease progression; this is biologically important because MIP-1␤ is a specific ligand for CCR-5, and CCR-5 mutations have been associated with protection from HIV-infection (in the homozygous state) and slower progression to AIDS (in the heterozygous state). In contrast, RANTES and MIP-1␣ also bind to other receptors (57).…”

“…Several studies have shown that activated peripheral blood mononuclear cells (PBMC) from HIV-exposed but uninfected individuals (26)(27)(28) and nonhuman primates protected from simian immunodeficiency virus challenge by certain vaccines (29-32) produced high levels of RANTES, MIP-1␣, and MIP-1␤. Other studies show an association between higher-production HIV-suppressive chemokines from activated PBMC and a more favorable clinical status in HIVϩ individuals (27,33,34). Taken together, these results merely could reflect the more robust immune responses found in clinically healthy subjects and implicate elevated chemokine levels as surrogate markers for disease status.…”

Chemokine immunobiology in HIV-1 pathogenesis

“…4 and 105]: these earlier studies should be interpreted with caution in light of the recent understanding that not only can chemokines be released from platelets during the collection procedure [106][107][108] but also that they bind to glycosaminoglycans on cell surfaces and other carbohydrate moieties in blood [109][110][111]. However, despite the discrepancies in the literature as cited above, it is our opinion that the preponderance of the more recent evidence indicates that decreasing levels of chemokine secretion are correlated with the severity of disease progression [100,112,113]. Particularly convincing are data from animal models showing an association between high circulating CC chemokine levels with sterilizing immunity in HIV-1-vaccinated macaques [114,115].…”

Higher macrophage inflammatory protein (MIP)-1α and MIP-1β levels from CD8+T cells are associated with asymptomatic HIV-1 infection

“…A specific immune response involving a high production of ␤ chemokines by CD4 ϩ T cells seems to play a role of protection in exposed uninfected individuals (32) and may contribute to the control of viral replication in long-term nonprogressors (33). Higher ␤-chemokine secretion by PBMCs has been described in nonprogressors compared with rapid progressors (34), and higher production of MIP-1␤ by PBMCs has been associated with an asymptomatic status and decreased risk of disease progression (35). Antigen-induced chemokine production is also significantly decreased in HIV ϩ subjects with AIDS compared with asymptomatic HIV ϩ subjects (36).…”