Effect of Bacterial Pneumonia on Lung Simian Immunodeficiency Virus (SIV) Replication in Alcohol Consuming SIV‐Infected Rhesus Macaques

Abstract

Background Opportunistic infections in HIV-infected persons have been shown to increase the rate of HIV replication. In populations where prophylaxis against Pneumocystis pneumonia is utilized, bacterial pneumonia is now the leading cause of lower respiratory tract infection in HIV+ patients. Our prior studies have shown that chronic alcohol consumption in simian demarcated immunodeficiency virus (SIV) infected rhesus macaques increases plasma viral load set point and accelerates progression to end-stage AIDS. While chronic alcohol abuse is well-known to increase the incidence and severity of bacterial pneumonia, the impact of alcohol consumption on local and systemic SIV/HIV burden during lung infection is unknown. Therefore, we utilized the macaque SIV infection model to examine the effect of chronic ethanol feeding on SIV burden during the course of pulmonary infection with Streptococcus pneumoniae, the most commonly identified etiology of bacterial pneumonia in HIV+ and HIV- persons in developed countries. Methods Alcohol was administered starting 3 months before SIVMac251 inoculation to the end of the study via an indwelling intragastric catheter to achieve a plasma alcohol concentration of 50–60 mM. Control animals received isocaloric sucrose. Four months after SIV infection, the right lung was inoculated with 2 × 106 CFU S. pneumoniae. Results Leukocyte recruitment into the lung, pulmonary bacterial clearance, and clinical course were similar between ethanol and control groups. While plasma SIV viral load was similar between groups post-pneumonia, chronic ethanol-fed macaques showed a prolonged increase in SIV RNA in bronchoalveolar lavage (BAL) fluid. Alveolar macrophages isolated from ethanol-fed macaques one day post-pneumonia showed greater nuclear factor kappa beta (NF-kB) activation. Conclusions This study indicates that chronic ethanol feeding results in enhanced local, but not systemic, SIV replication following pneumococcal pneumonia. Increased NF-kB activity in the setting of chronic ethanol ingestion may play a mechanistic role in this observation.

Behavioral, Metabolic, and Immune Consequences of Chronic Alcohol or Cannabinoids on HIV/AIDs: Studies in the Non-Human Primate SIV Model

“…The increase in viral replication following CBA could lead to a decreased capacity to control viral reactivation during opportunistic infections. In support of this hypothesis, results from our studies show that S. pneumoniae inoculation results in prolonged viral replication in the infected lungs of CBA-administered SIV-infected macaques, as compared to that of SIV-infected controls (Nelson et al 2013). Increased localized HIV replication, particularly in alveolar macrophages and CD4 + cells, has been reported to increase viral mutations and promote viral escape from latent reservoirs (Nelson and Bagby 2011).…”

Ethanol Impairs Mucosal Immunity against Streptococcus pneumoniae Infection by Disrupting Interleukin 17 Gene Expression

“…ART was continued throughout the study period. At four and a half months of SIV infection, animals were inoculated with 2 ϫ 10 6 CFU of S. pneumoniae, serotype 19F (ATCC 6319), into a subsegment of the lower lobe of the right lung using a pediatric bronchoscope as previously described (14). Monkeys underwent bronchoscopies and bronchial brushings prepneumonia and day 1 postpneumonia.…”

“…As the lung epithelium is a major site of chemokine production during bacterial pneumonia (12), we examined the effect of ethanol on gene expression in the airway epithelium during experimental S. pneumoniae infection in a nonhuman primate model of ethanol consumption and pneumococcal infection (13,14). We analyzed bronchial brush samples for gene expression using RNA sequencing and determined that ethanol consumption was associated with downregulation of IL-17 inducible genes in the bronchial epithelium 24 h postinfection.…”

Biomedical Consequences of Alcohol Use Disorders in the HIV-Infected Host

“…Opportunistic infections, such as pneumonia, can increase viral replication thereby accelerating progression to AIDS. Our studies [30] have shown that direct intrapulmonary infection with S. pneumoniae leads to prolonged viral replication in infected lungs of SIV-infected alcohol-fed animals as compared to that of SIV-infected controls. The most likely site of viral replication is the alveolar macrophage [31].…”