Modeling and treating chronic HIV-induced lung infections

About This Grant

PROJECT SUMMARY: People Living with HIV (PLWH) are at increased risk of both acute and chronic lung diseases. Although the use of effective anti-retroviral therapy (ART) has diminished the burden of infectious lung disease, morbidity and mortality from chronic lung diseases in PLWH has been steadily increasing. HIV infection is associated with increased risks of pneumonia from bacteria, viruses, fungi and parasites. More importantly, bacterial pneumonia (caused by Streptococcus pneumoniae) is one of the most frequent respiratory infections that cause severe or very severe symptoms in both ART-naive and ART-exposed children infected with HIV. While the clinical consequences of HIV-associated lung infections in PLWH are well documented, knowledge on cellular and molecular mechanisms leading to HIV-associated lung disease is very limited. Hence, a deeper understanding on immune mechanisms that lead to increased susceptibilities to lung infections may define potentially new therapeutic targets for treating PLWH. To this end, the research proposed here aims to unravel the physiologic impact of HIV infection on dendritic cell (DC) differentiation and determine DC functions during respiratory infections. The major hypothesis of our proposed research is that chronic HIV-1 infection results in increased susceptibilities to microbial co-infections in the lungs, due exaggerated inflammatory signals- and HIV auxiliary proteins- induced DC defects. The rationale is that ongoing chronic inflammation induced in response to HIV and consistent circulation of HIV accessory proteins suppress the differentiation program of DCs in the periphery, which eventually leads to reduced DC numbers and functions in the lungs during life-threatening respiratory infections. To test our hypothesis, we will use a combination of xenotransplantation, in-vitro culture, molecular cell biology, biochemical & immunology studies. In the first specific aim, we would test if HIV-1 infection suppressed DC differentiation pathways and identify the cytokine(s) responsible for HIV-1-induced DC differentiation defects. In the second specific aim, we would identify if the presence of HIV accessory proteins impairs DC differentiation and molecular program. In the third specific aim, we would evaluate if chronic HIV infection results in impaired immune differentiation and determine if human DC functions are compromised during respiratory infections. Studies proposed in Aims 1, 2 & 3 are complimentary and informed by the data of each other, but not dependent on the outcome of the other Aims. A thorough knowledge on mechanisms through which HIV-infection induces DC defects and increased susceptibilities to respiratory infections would be essential in treating HIV- associated immunodeficiencies. In addition, our studies are designed to evaluate novel treatment strategies to restore immune differentiation and functions during chronic HIV infection.