Rapid Immune Restoration and Lung Injury in HIV/TB



 DESCRIPTION (provided by applicant): By decimating Mycobacterium tuberculosis (Mtb)-specific immune function, HIV-1 infection dramatically increases the risk of tuberculosis (TB), such that nearly 15% of all TB cases and 25% of global TB deaths are HIV-associated. Although TB is a treatable disease, it is associated with significant chronic morbidity among those who are cured. In pulmonary TB (pTB), for example, over half of patients have pulmonary function impairment despite achieving microbiologic cure. While some patients achieve complete radiographic and symptomatic resolution, others are left with permanent distortion of the airways, persistent cough and severe chronic breathlessness. Human studies to date have not focused on identifying modifiable biological factors that determine long-term functional outcome. This is a critical knowledge gap because understanding this relationship could inform development of novel host-directed therapies designed to decrease morbidity in this globally important disease. HIV/TB is a disease state characterized by immunosuppression and high levels of immune activation and inflammation. While successful TB and HIV treatment eventually reverses these effects, dramatic increases in Mtb-specific immune function, inflammatory cytokines and circulating proteases involved in lung collagen degradation frequently occur in patients with HIV/pTB who initiate antiretroviral therapy (ART). Anecdotal reports have indicated that ART-associated cellular immune restoration can lead to overt development of pulmonary cavitation and worsening lung function. These data challenge the notion that the process of lung destruction in TB stops, and healing begins, after pTB treatment initiation. We hypothesize that in HIV/pTB an untoward and modifiable effect of rapid, treatment-related reversal of immunosuppression is worsening of lung injury. In this proposal, we will test this hypothesis via two aims set within a single prospective cohort study in South Africa. Specific Aim 1 will test the hypothesis that ART initiation is associated with increased pulmonary inflammation early after ART initiation. Pulmonary inflammation will be serially assessed by 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET-CT), which can visually localize inflammation in the lung, prior to and after ART initiation. Specific Aim 2 will test the hypothesis that more rapid immune restoration on ART is associated with permanently impaired lung function. By studying immunologic mechanisms associated with incident lung damage during TB treatment, this project will increase understanding of TB-associated lung injury more broadly and will directly inform future trials of host-directed therapies in this disease.