CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

660 EFFECT OF HIV INFECTION ON ALPHA-1 ANTITRYPSIN FUNCTION: ROLE IN EMPHYSEMA? Sarah E. Stephenson 1 , Engi F. Attia 2 , Carole L. Wilson 1 , Cherry Wongtrakool 3 , Kristina Crothers 2 , Irina Petrache 4 , Lynn M. Schnapp 1

1 Med Univ of South Carolina, Charleston, SC, USA, 2 Univ of Washington, Seattle, WA, USA, 3 Emory Univ, Atlanta, GA, USA, 4 Natl Jewish Hlth, Univ of Colorado, Denver, CO, USA Background: Emphysema is one of the most common lung diseases in HIV+ patients and is characterized by reduced diffusing capacity for carbon monoxide (DLCO). Pathogenesis of HIV-associated emphysema remains unclear; however, the radiographic distribution with greater lower lobe involvement and earlier age at presentation in HIV+ patients are similar to patients with deficiency of alpha-1 antitrypsin (A1AT), a key elastase inhibitor in the lung. We hypothesized that HIV is associated with decreased A1AT activity and explored whether decreased A1AT activity is associated with reduced DLCO and radiographic emphysema. Methods: The Examinations of HIV Associated Lung Emphysema (EXHALE) study enrolled 196 HIV+ and 165 HIV- smoking-matched subjects between 2009-2012. Subjects underwent pulmonary function tests, chest CT scans and phlebotomy; a subset (n=53) underwent research bronchoscopy. We analyzed plasma and bronchoalveolar lavage fluid (BALF) from 22 HIV+ and 31 HIV- patients. Differential cell counts and pro-inflammatory cytokines were measured in BALF. We measured A1AT levels in plasma and BALF by ELISA. In BALF, we assessed anti-elastase activity as an indicator of A1AT function and measured oxidized and polymerized A1AT by western blot. Differences in levels of markers were compared by HIV status and presence of lung disease, defined by DLCO <60% predicted or any radiographic emphysema on chest CT, using Wilcoxon rank sum tests. Results: In the BALF of HIV+ patients, neutrophils and granulocyte colony stimulating factor (G-CSF), a chemoattractant for neutrophils, tended to be elevated compared to HIV- patients (Table). Total A1AT was increased in BALF, but not in plasma, of HIV+ compared to HIV- patients. Concurrently, we detected decreased anti-elastase activity by A1AT in BALF in HIV+ compared to HIV- patients, suggesting impaired A1AT function. We detected modifications of A1AT, including polymerized and oxidized forms, in HIV+ patients, which may account for decreased A1AT anti-elastase activity. BALF A1AT and elastase activity did not differ by DLCO or emphysema. However, those with lower lobe emphysema had greater median BALF A1AT (1105 [IQR 490-1162] vs 582 [205-1089]; p=0.08) and a trend for increased elastase activity (0.88 [0.52-0.96] vs 0.58 [0.21-0.88]; p=0.1). Conclusion: These findings suggest that in the lungs of HIV+ patients, post-translational modifications of A1AT produce a functional deficiency of this critical elastase inhibitor, which may contribute to emphysema development.

Poster and Themed Discussion Abstracts

661 HIV AND CIRCULATING LEVELS OF PRO-SURFACTANT PROTEIN B AND SURFACTANT PROTEIN D Meredith S. Shiels 1 , Gregory D. Kirk 2 , M. Brad Drummond 3 , Dilsher Dhillon 4 , Samir Hanash 4 , Ayumu Taguchi 4 , Eric A. Engels 1

1 NCI, Rockville, MD, USA, 2 Johns Hopkins Univ, Baltimore, MD, USA, 3 Univ of North Carolina at Chapel Hill, Chapel Hill, NC, USA, 4 MD Anderson Cancer Cntr, Houston, TX, USA Background: Lung cancer risk is elevated 2-3 times in people with HIV compared to the general population after controlling for smoking. It has been hypothesized that chronic pulmonary infections or inflammation may contribute to elevated risk. In a cohort of HIV-infected and uninfected adults, we evaluated serum levels of pro-surfactant protein B (pro-SFTPB) and surfactant protein D (SFTPD), two markers of lung inflammation and damage that are prospectively associated with lung cancer. Methods: Circulating levels of pro-SFTPB and SFTPD were measured in the serum of 500 HIV-infected and 300 uninfected people enrolled in the Study of HIV Infection in the Etiology of Lung Disease. We estimated geometric mean surfactant protein levels by HIV status, adjusted for age, race, sex, and smoking status. Among HIV-infected individuals, we also assessed surfactant protein levels by CD4 cell counts, HIV RNA viral load and current HAART use. Results: Pro-SFTPB levels were positively associated with increasing age, current smoking, cigarettes/day and chronic obstructive pulmonary disease while SFTPD levels were positively associated with current smoking and white race. Pro-SFTPB and SFTPD levels were weakly correlated (r=0.20). Pro-SFTPB levels were significantly higher among HIV- infected compared to HIV-uninfected participants (adjusted geometric mean: 19.7 vs. 16.7 ng/mL; p=0.03). Pro-SFTPB levels were higher among those with lower CD4 cell counts (geometric mean 32.1 vs. 19.7 ng/mL for CD4 <200 vs. ≥500 cells/mm3; p-trend=0.002), higher HIV RNA viral loads (29.8 vs. 22.3 ng/mL for <10,000 copies/mL vs. undetectable levels; p-trend=0.07), and among those not currently being treated with HAART (28.2 vs. 19.2 ng/mL for untreated vs. treated individuals; p=0.02; Figure). However, no difference in SFTPD levels was observed by HIV status (85.8 vs. 93.6 ng/mL; p=0.15) or across categories of CD4 cell count (p-trend=0.99), HIV RNA viral load (p-trend=0.76) or current HAART use (p=0.78). Conclusion: In summary, HIV-infected people manifest elevated levels of pro-SFTPB, but not SFTPD, compared to uninfected people, independent of tobacco use. Pro-SFTPB levels are further increased in association with declining CD4 cell count, high HIV RNA viral load, and in the absence of HIV treatment. As pro-SFTPB is a predictor of lung cancer risk in the general population, these findings provide support for a role of pulmonary inflammation and lung damage in explaining the increased risk of lung cancer among HIV-infected people.

CROI 2017 285