Anti-nerve growth factor Ab abrogates macrophage-mediated HIV-1 infection and depletion of CD4⁺T lymphocytes in hu-SCID mice

Abstract

Infection by HIV-1 causes persistent, long-term high virus production in macrophages. Major evidence, both in humans and in primate models, shows the crucial role of macrophages in sustaining virus production and in mediating a cytopathic effect on bystander CD4 ؉ T lymphocytes and neuronal cells. In the present study, we used severe combined immunodeficient (SCID) mice engrafted with human peripheral blood lymphocytes (hu-PBL-SCID mice) to investigate the in vivo effect of HIV-1-infected macrophages on virus spread and CD4 ؉ T lymphocyte depletion, and the ability of a mAb against nerve growth factor (NGF, a neurokine essential for the survival of HIV-1-infected macrophages) to suppress the pathogenetic events mediated by infected macrophages. Injection of mice with as few as 500 HIV-exposed macrophages causes (i) complete depletion of several millions of autologous CD4 ؉ T lymphocytes, (ii) sustained HIV viremia, and (iii) spreading

HIV-1 Tat Interactions with p300 and PCAF Transcriptional Coactivators Inhibit Histone Acetylation and Neurotrophin Signaling through CREB

“…HIV-1-infected macrophages and monocytes produce significantly elevated levels of soluble NGF and express both high affinity (p140 TrkA ) and low affinity (p75 NTR ) NGF receptors on their surfaces (69). Indeed, a monoclonal antibody against NGF prevented HIV-1 replication and CD4 ϩ T-cell loss in severe combined immunodeficient mice engrafted with human peripheral blood lymphocytes, supporting an essential role for NGF during HIV-1 pathogenesis resulting in immune suppression (70). Nerve growth factor protects HIV-1-infected macrophages and monocytes against apoptosis through NF-B-dependent signaling/transcription pathways (71).…”

“…BDNF receptor (p145 TrkB ) expression is also increased in post-mortem CNS tissues from neuro-AIDS patients (95). NGF functions as an autocrine/paracrine survival factor produced by HIV-1-infected macrophages and monocytes (69,70). HIV-1-infected macrophages and monocytes produce significantly elevated levels of soluble NGF and express both high affinity (p140 TrkA ) and low affinity (p75 NTR ) NGF receptors on their surfaces (69).…”

HIV-1 dual/mixed tropic isolates show different genetic and phenotypic characteristics and response to maraviroc in vitro

“…Medium for U87MG-CD4 + /CXCR4 + and U87MG-CD4 + /CCR5 + was supplemented with 400 g/ml G418 (Sigma-Chemicals). Peripheral blood mononuclear cells (PBMC) were obtained by centrifuging whole-blood from healthy HIVseronegative blood-donors on a Ficoll-Hypaque density-gradient as previously described (Aquaro et al, 2001(Aquaro et al, , 2004Garaci et al, 2003;Perno et al, 1998). MT-2 cell-line expressing CD4-and CXCR4-receptors were maintained in RPMI1640 (Euroclone) with addition of 10% FBS at 37 • C with 5% CO 2 .…”

Macrophages and HIV-1: dangerous liaisons

“…This survival effect involves bcl2, bcl-xL and bfl1 anti-apoptotic molecules (la Sala et al, 2000) and is abrogated by NGF neutralisation leading to p75NTR-mediated apoptosis (Caroleo et al, 2001;Garaci et al, 1999). This could be a powerful mechanism for maintaining viral replication (Garaci et al, 2003), especially in the restrictive CNS milieu, and illustrates exactly how HIV uses endogenous molecules for its own benefit.…”