Human immunodeficiency virus (HIV) infection is associated with a 24- to 28-fold increase in active tuberculosis (TB), with alveolar macrophages (AMs) subject to infection by both HIV and Mycobacterium tuberculosis (Mtb). The contribution of AMs to the HIV reservoir in untreated and antiretroviral (ART)-treated people with HIV is not well understood, nor is the contribution of directly infected or bystander AMs to the cellular dysfunction seen in HIV infected lungs. The mechanisms by which HIV infection increases risk of active TB infection are also unclear. Our preliminary data from transcriptional analysis of AMs from individuals with untreated HIV infection and healthy controls suggest that HIV induces AMs to upregulate specific sets of inflammatory genes, including CCL2, which recruits monocytes to tissues. We observed HIV-associated upregulation of CCL2 transcripts in AMs and increased CCL2 protein levels in bronchoalveolar lavage (BAL) fluid. CCL2 has been associated with increased susceptibility to active TB in humans, mice and zebrafish, but HIV-induced CCL2 production has not been linked to increased risk of active TB. We propose to study BAL samples from HIV-infected and -uninfected individuals and use in vivo model systems in order to assess the frequency and impact of direct and indirect HIV infection on AMs and the mechanisms behind HIV-induced CCL2 production and its role in susceptibility to TB. To accomplish this goal, we will first study the frequency of HIV-infected AMs and measure the effects of different types of HIV infection and exposure on AMs. Next, we will study changes in macrophage recruitment in the lungs of HIV-infected people and model CCL2-induced macrophage recruitment in Mtb-infected mice to understand how this may modulate the risk of active TB. The results of these aims will enable us to define the effects of HIV on AMs, elucidate a key mechanism that may drive HIV-associated TB, and identify novel host-directed therapeutic targets for TB.
Human immunodeficiency virus (HIV) infection is associated with a 24- to 28- fold increase in active tuberculosis (TB), with alveolar macrophages (AMs) subject to infection by both HIV and Mycobacterium tuberculosis. We aim to study the frequency of HIV-infected AMs, to measure the effects of HIV infection on AMs, and to study changes in macrophage recruitment in the lungs of HIV-infected people to understand how this may modulate risk of active TB. It is our hope that this work will identify the contribution of AMs to the HIV reservoir, which is important to know for HIV cure efforts, and that it will identify a host-directed therapy to prevent active TB in people with HIV.
