Postgenomic up-regulation of CCL3L1 expression in HTLV-2-infected persons curtails HIV-1 replication.
Leukocytes of persons coinfected with HTLV-2 and HIV-1 secrete chemokines that prevent CCR5-dependent (R5) HIV-1 infection of CD4+ T cells and macrophages, with HTLV-2-induced MIP-1alpha as dominant HIV-1 inhibitory molecule. Two nonallelic genes code for CCL3 and CCL3L1 isoforms of MIP-1alpha, and the population-specific copy number of CCL3L1 exerts a profound effect on HIV-1 susceptibility and disease progression. Here, we demonstrate that CCL3L1 is secreted spontaneously by leukocytes of HTLV-2-infected persons and superinduced when cells of HTLV-2/HIV-1 multiply exposed-uninfected seronegative (MEU) persons were stimulated with HIV-1 Env peptides. The CCL3L1 median copy number in MEU, HTLV-2/HIV-1-coinfected long-term nonprogressors (LTNPs) and HIV-1-monoinfected LTNPs were 1, 2, and 3, respectively. An increased CCL3L1/CCL3 mRNA ratio versus PHA-activated healthy leukocytes was observed in both HIV-1-monoinfected LTNPs and in HTLV-2/HIV-1(MEU) subjects. An additional potential correlate of HTLV-2 infection was a rapid and persistent leukocyte secretion of GM-CSF and IFN-gamma, 2 cytokines endowed with CCR5 down-regulation capacity. This study confirms a crucial protective role of CCL3L1 from both HIV infection and disease progression, highlighting a previously not described functional up-regulation of this chemokine variant in both HIV-positive and -negative persons infected with HTLV-2.
Pilotti
Elisabetta
E
Department of Clinical Medicine, Nephrology, and Health Sciences, University of Parma, Italy.
Elviri
Lisa
L
Vicenzi
Elisa
E
Bertazzoni
Umberto
U
Re
Maria Carla
MC
Allibardi
Sonia
S
Poli
Guido
G
Casoli
Claudio
C
D000328:Adult; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004198:Disease Susceptibility; D005260:Female; D015870:Gene Expression; D015894:Genome, Human / Q000235:genetics; D005838:Genotype; D015497:HIV-1 / Q000502:physiology*; D015491:HTLV-II Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D015367:Human T-lymphotropic virus 2 / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D014779:Virus Replication
C492767:CCL3L1 protein, human; D019742:Chemokines, CC; D009687:Nuclear Proteins; D020033:Protein Isoforms; D014157:Transcription Factors