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

Stefano Aquaro^*, Enrico Garaci^*, Filippo Belardelli^†,Caterina Lapenta^†, Alessandra Amendola^‡, Massimo Spada^†, Sonia Covaceuszach^§, Carlo-Federico Perno^*. ^*Dept. of Experimental Medicine and Biochemical Sciences, University of Rome “Tor Vergata”; ^†Istituto Superiore di Sanità (ISS); ^‡INMI “L. Spallanzani”; ^§Lay Line Genomics S.p.A. (LLG); Rome (Italy).

Background: Infection by HIV-1 causes a persistent, long-term high virus production in macrophages. Major evidences, both in humans and in primate models, show the crucial role of macrophages in sustaining virus production, and in mediating a cytopathic effect upon bystander CD4+ T-lymphocytes and neuronal cells. In the this study we investigated the in vivo effect of HIV-1-infected macrophages upon virus spread and CD4+ T-lymphocyte depletion, and the ability of a monoclonal antibody 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. Material and Methods: SCID mice were reconstituted with human (hu) peripheral blood leukocytes (PBLs) obtained from the peripheral blood of healthy donors screened for HIV-1 (hu-PBL-SCID mice). Hu-PBL-SCID mice were injected intraperitoneally with HIV-infected or mock-infected autologous macrophages. In selected experiments a monoclonal anti-NGF antibody were inoculated intraperitoneally in mice. CD4+ T-lymphocyte depletion, HIV-1 viremia, NGF production, and HIV-1 infection in mice organs and tissue were measured at different time points. Results: 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 of HIV-1-DNA in mouse lymphoid organs. By contrast, in vivo treatment with anti-NGF antibody completely abrogates all effects mediated by HIV-infected macrophages. Taken together, the results demonstrate the remarkable power of macrophages in sustaining the in vivo HIV-1 infection, and that such phenomenon can be specifically abrogated by anti-NGF antibody. This may open new perspectives of experimental approaches aimed at selectively eliminating persistently-infected macrophages from the body of HIV-infected patients.