Divergent regulation of HIV-1 replication in PBMC of infected individuals by CC chemokines: suppression by RANTES, MIP-1alpha, and MCP-3, and enhancement by MCP-1.
We investigated the role of different CC chemokines, including regulated upon activation normal T cell expressed and secreted (RANTES), macrophage inflammatory protein-lalpha (MIP-1alpha), monocyte chemotactic protein-1 (MCP-1), and MCP-3 on virus replication in cultures established from CD8+ T cell-depleted peripheral blood mononuclear cells (PBMC) of HIV-infected individuals that were either cocultivated with allogeneic T cell blasts (ATCB) of uninfected individuals or directly stimulated by mitogen plus interleukin-2. RANTES was the only chemokine that showed a clear-cut suppressive effect on HIV replication in both culture systems, although inhibitory effects were frequently also observed with MIP-1alpha, MCP-3, and, occasionally, with MCP-1. In contrast, MCP-1 frequently enhanced HIV production in most patients' cultures or cocultures that were characterized by secreting relatively low levels (<20 ng/mL) of MCP-1. When CD8-depleted PBMC of HIV+ individuals were cocultivated with ATCB of uninfected healthy donors, a positive correlation was observed between MCP-1 concentrations and the enhancement of HIV-1 replication occurring after depletion of CD8+ cells from donors' cells. Depletion of CD14+ cells (monocytes) from ATCB resulted in the down-regulation of virus replication during co-cultivation with CD8-depleted PBMC of infected individuals. Of interest, MCP-1 up-regulated HIV production in these CD14-depleted ATCB cocultures. Altogether these observations suggest that MCP-1 may represent an important factor enhancing HIV spreading, particularly in anatomical sites, such as the brain, where infection of macrophages and microglial cells plays a dominant role.
Vicenzi
E
E
AIDS Immunopathogenesis Unit, San Raffaele Scientific Institute, Milan, Italy.
Alfano
M
M
Ghezzi
S
S
Gatti
A
A
Veglia
F
F
Lazzarin
A
A
Sozzani
S
S
Mantovani
A
A
Poli
G
G
D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology; D018932:Chemokine CCL2 / Q000276:immunology / Q000494:pharmacology / Q000502:physiology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D054410:Chemokine CCL7; D019742:Chemokines, CC / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D016207:Cytokines; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000502:physiology / Q000821:virology*; D019402:Macrophage Inflammatory Proteins / Q000276:immunology / Q000502:physiology; D008297:Male; D018945:Monocyte Chemoattractant Proteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
C515450:CCL7 protein, human; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054410:Chemokine CCL7; D019742:Chemokines, CC; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D018945:Monocyte Chemoattractant Proteins; D011994:Recombinant Proteins