We synthesized and systematically tested a library of RANTES isoforms for their ability to inhibit inflammatory signaling and prevent HIV-1 infection of primary human cells.
We analysed the distribution of SNPs in chemokines (CCL3, CCL4, CCL5, CXCL12) and chemokine receptor (CXCR6) genes, in 268 HIV-1 infected patients (HIV-1+) and 221 healthy controls from Northeast Brazil, and their possible connection with susceptibility to HIV-1 infection.
The frequency of RANTES -403A allele was significantly lower in HIV-1 patients than in healthy blood donors (p=0.0005) and HESN group (p=0.035), which implied the association between A allele and reduced HIV-1 infection risk.
We studied single-nucleotide polymorphisms (SNPs) in genes encoding three CCR5 ligands (CCL3 (MIP-1a), CCL4 (MIP-1b)and CCL5 (RANTES)) along with an adjacent gene encoding a CCR2ligand (CCL2 (MCP-1)) to identify candidate markers for HIV-1 infection and pathogenesis.
This work provides proof of principle for the use of L. jensenii-produced C1C5 RANTES to block HIV-1 infection of CD4(+) T cells and macrophages, setting the basis for the development of a live anti-HIV-1 microbicide targeting CCR5 in an antagonistic manner.
The In1.1C single nucleotide polymorphism (SNP) allele results in reduced RANTES transcription, which is associated with increased frequency of HIV-1 infection, and rapid progression to AIDS among HIV-1-infected individuals.
The products of these genes and of CCL5 (encoding RANTES, i.e., regulated on activation, normal T expressed and secreted) can block or interfere with human immunodeficiency virus type 1 (HIV-1) infection through competitive binding to chemokine (C-C motif) receptor 5 (CCR5).
However, other mutations in the CCR5, CCR2, CX(3)CR1, CXCL12 (SDF1), and CCL5 (RANTES) genes have been identified and associated with host resistance and/or susceptibility to HIV-1 infection and disease progression.
We conducted a nested case-control study of African Americans (266 HIV-1 seroconverter cases and 532 seronegative controls from the AIDS Link to Intravenous Experience cohort), to examine the association between 50 single-nucleotide polymorphisms (SNPs) in 9 candidate genes (CCR5, CCR2, RANTES, MIP1A, MCP2, IL10, IFNG, MCSF, and IL2) and susceptibility to HIV-1 infection.
These genes encode a host of proteins with divergent functions in a variety of cellular processes including apoptosis (FAS, Fas ligand, PIN, HSP90beta, bcl-2, bcl-x), cell signal transduction (Ras, RGS1, IRF-1, STAT3), receptor-mediated signaling transduction (CD71, CD69, CD3delta), cell cycle and growth (c-myc, cytokines, kinase), transcriptional regulation (EWS, CREB-2), and chemotaxis (beta-chemokines, RANTES), supporting the general effects of HIV-1 infection on cells of different origin.
However, the CCR5-59029A, CCR2-64I, stromal cell-derived factor (SDF)-1-3'A, RANTES (regulated on activation, normally T cell-expressed and -secreted)-403A, and RANTES-28G polymorphisms were not associated with resistance to HIV-1 infection.
Three SNPs in the RANTES gene region on chromosome 17 (403A in the promoter, In1.1C in the first intron, and 3'222C in the 3' untranslated region) are associated with increased frequency of HIV-1 infection.
We found that stimulation with GM-CSF or M-CSF induced macrophage inflammatory proteins (MIP-1alpha and MIP-1beta) and augmented RANTES expression, after HIV-1 infection of microglia.
Expression of CC chemokine receptor 5 (CCR5), the major coreceptor for HIV-1 cell entry, and its ligands (e.g., RANTES and MIP-1alpha) is widely regarded as central to the pathogenesis of HIV-1 infection.
We found an increased mRNA expression of monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1 alpha and MIP-1 beta, and RANTES by macrophages after HIV-1 infection.
We observed spontaneous production of significant levels of MIP-1alpha and -1beta and, to a lesser extent, RANTES, from individuals infected with HTLV-II alone or with concomitant HIV-1 infection.
These results suggested that the M23-g3p might mimic the CCR5-binding domain shared by beta-chemokines, MIP-1alpha, MIP-1beta, and RANTES as well as the HIV-1 infection.
Chronic HIV-1 infection of U937 monocytic cells increased the expression of RANTES, MIP-1alpha, MIP-1beta, and IL-8 chemokine genes, but strongly inhibited PMA/PHA- and TNFalpha-induced MCP-1 gene transcription.
Even though it achieved lower circulating concentrations than AOP-RANTES (75 to 96 pM as opposed to 460 pM under our experimental conditions), NNY-RANTES was more effective in preventing HIV-1 infection.
This relative resistance to HIV-1 infection did not extend to T cell line-adapted or syncytium-inducing (SI) primary viral isolates, was restricted by the envelope glycoprotein, and was associated with an increased production of the C-C chemokines RANTES, MIP-1alpha, and MIP-1beta.