Pro-inflammatory response and defective bactericidal activity by Mycobacterium tuberculosis/HIV-1 co-infected human macrophages (INC7P.421)

Abstract

Abstract Mycobacterium tuberculosis (M.tb), the etiological agent of tuberculosis (TB), is the leading cause of death in people living with Human Immunodeficiency Virus (HIV). In contrast to most other opportunistic infections, susceptibility to M.tb occurs prior to significant loss of peripheral CD4+T cells in people with HIV. The molecular basis for pathogen synergy that leads to an aggressive course of TB in those with HIV-1 infection is poorly defined. The primary objective of this study is to determine how HIV-1 alters the host macrophage innate immune response to M.tb infection. Primary human monocyte-derived macrophages, alveolar macrophages from human donor bronchoalveolar lavage, and our recently developed humanized mouse model of M.tb/HIV co-infection were used for in vitro and in vivo studies. Preliminary results demonstrate that HIV-1 (JR-CSF)/M.tb (H37Rv) co-infection results in greater cell death and increased expression of pro-inflammatory cytokines and chemokines (e.g. IL-1β, IL-6, MCP) compared to mono-infection with either HIV-1 or M.tb. A corresponding increase in leukocyte recruitment into the lungs of M.tb-infected humanized mice was observed in animals with HIV-1 infection and coincided with greater mycobacterial dissemination. These studies suggest that inappropriate inflammatory responses by host macrophages may contribute to dysfunctional host immunity to M.tb in those with concurrent HIV-1 infection.