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

Abstract

The ␤-chemokines RANTES, macrophage inflammatory protein (MIP)-1␣, and MIP-1␤ suppress infection by macrophage-tropic strains of HIV and simian immunodeficiency virus (SIV) by binding and down-regulating the viral coreceptor, CCR5. Accordingly, we have examined whether higher levels of CCR5 ligands are associated with a more favorable clinical status in AIDS. A cross-sectional study of 100 subjects enrolled in the Multicenter AIDS Cohort Study at the Baltimore site was conducted to measure chemokine production and lymphocyte proliferation by peripheral blood mononuclear cells (PBMC). Statistical analyses of the data revealed that the production of HIV-suppressive ␤-chemokines by HIV antigenstimulated PBMC was significantly higher in HIV-positive subjects without AIDS compared with subjects with clinical AIDS. Increased chemokine production was also correlated with higher proliferative responses to HIV antigens. Both parameters were significantly lower in the AIDS versus non-AIDS group. Notably, significantly higher levels of MIP-1␣ were also observed with unstimulated PBMC from seronegative subjects at risk for HIV infection released as compared with seropositive and non-Multicenter AIDS Cohort Study seronegative subjects. The association of chemokine production with antigen-induced proliferative responses, more favorable clinical status in HIV infection, as well as with an uninfected status in subjects at risk for infection suggests a positive role for these molecules in controlling the natural course of HIV infection.lymphocyte proliferation

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

“…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). In accordance with these findings, sustained suppression of plasma HIV RNA is associated with an increase in the production of mitogen-induced MIP-1␣ and MIP-1␤ (37).…”

Purification of a Modified Form of Bovine Antithrombin III as an HIV-1 CD8+ T-cell Antiviral Factor

“…: 617-726-5710; Fax: 617-726-5651; E-mail: luster@helix.mgh.harvard.edu. 1 The abbreviations used are: HIV, human immunodeficiency virus; SIV, simian immunodeficiency virus; SHIV, simian-human immunodeficiency virus; ATIII, antithrombin III; CAF, CD8 ϩ T-cell antiviral factor(s); TCID 50 , 50% tissue culture infective dose; ID 50 , protein concentration causing a 50% decrease in virus antigen production; CTL, cytotoxic T-lymphocytes; BSA, bovine serum albumin; R20, 20% heatinactivated fetal calf serum; HPLC, high-pressure liquid chromatography; NF-B, nuclear factor B; ELISA, enzyme-linked immunosorbent assay; S, stressed; R, relaxed; L, latent. activity was purified 215 times, and after the Superdex 200 column 909 times (16).…”

“…Soluble inhibitory factors produced by CD8 ϩ T-cells have been shown to inhibit HIV-1 1 replication and may play a critical role in vivo in antiviral host defense (1). These inhibitory factors include CC-chemokines (2)(3)(4), which bind to the CCR5 coreceptor and inhibit R5 viral entry into cells (1) (5-7), as well as less well characterized soluble factor(s) produced by CD8 ϩ T-cells and termed CD8 ϩ T-cell antiviral factor(s) (CAF), which are capable of inhibiting both R5 and X4 HIV-1 (8 -15).…”

Soluble factors from T cells inhibiting X4 strains of HIV are a mixture of β chemokines and RNases

“…Although the dominant role of CCR5-binding chemokines as CD8-derived and CD4-derived HIV-suppressive factors has been widely confirmed (11)(12)(13), it is also clear that CD8 + and CD4 + T cells produce a complex array of molecules with antiviral activity, some of which are active against the X4 isolates of HIV-1 and awaited discovery (19). Our goal here was to identify the HIV suppressor factor(s) that selectively suppress X4 HIV strains.…”

“…This suggested that such factor(s) may be important in delaying or preventing disease progression (7). Our group identified the β chemokines, macrophage inflammatory protein (MIP)-1α, MIP-1β, and regulated-on-activation normal T-cell expressed and secreted (RANTES), as major mediators of the CD8 suppressive activity against R5 HIV-1 isolates (8) that depend upon CC chemokine receptor (CCR)5 for entry (9), and, later, we and others showed that levels of some correlated with protection against infection, as well as with an asymptomatic clinical status in HIV infection (10)(11)(12)(13)(14). Our group and others also reported that CD4 + T cells secreting antiviral CCR5 ligands are self-protected against infection with R5 virus during the primary immune response in vitro (15)(16)(17)(18).…”