Current Antiretroviral Therapy Era Research Articles

Monocyte Mobilization, Activation Markers, and Unique Macrophage Populations in the Brain: Observations from SIV Infected Monkeys Are Informative with Regard to Pathogenic Mechanisms of HIV Infection in Humans

Non-human primate models of AIDS and neuroAIDS have been useful to study AIDS in humans in general and neuroAIDS in particular. Important information concerning target cells of infection, mechanisms of immune activation and pathology and cell traffic has been made in non-human primate models. To date observations in SIV infected monkey models have predicted or paralleled monocyte/macrophage biology with HIV infection and neuroAIDS. In this brief review we discuss a CD8+ T lymphocyte depletion model of rapid AIDS which results in a high incidence of SIV encephalitis. Specifically we review recent observations we have made using this model concerning monocyte turnover, monocyte/macrophage activation, macrophage derived biomarkers of disease and novel therapeutic approaches to AIDS and CNS pathology. Importantly, all observations made in the rapid model of AIDS discussed here are important and relevant to HIV infection of humans, even in the current era of anti-retroviral therapy that maintains HIV in plasma below the limit of detection.

Human Immunodeficiency Virus Infection of Human Astrocytes Disrupts Blood-Brain Barrier Integrity by a Gap Junction-Dependent Mechanism

HIV infection of the CNS is an early event after primary infection, resulting in neurological complications in a significant number of individuals despite antiretroviral therapy (ART). The main cells infected with HIV within the CNS are macrophages/microglia and a small fraction of astrocytes. The role of these few infected astrocytes in the pathogenesis of neuroAIDS has not been examined extensively. Here, we demonstrate that few HIV-infected astrocytes (4.7 ± 2.8% in vitro and 8.2 ± 3.9% in vivo) compromise blood-brain barrier (BBB) integrity. This BBB disruption is due to endothelial apoptosis, misguided astrocyte end feet, and dysregulation of lipoxygenase/cyclooxygenase, BK(Ca) channels, and ATP receptor activation within astrocytes. All of these alterations in BBB integrity induced by a few HIV-infected astrocytes were gap junction dependent, as blocking these channels protected the BBB from HIV-infected astrocyte-mediated compromise. We also demonstrated apoptosis in vivo of BBB cells in contact with infected astrocytes using brain tissue sections from simian immunodeficiency virus-infected macaques as a model of neuroAIDS, suggesting an important role for these few infected astrocytes in the CNS damage seen with HIV infection. Our findings describe a novel mechanism of bystander BBB toxicity mediated by low numbers of HIV-infected astrocytes and amplified by gap junctions. This mechanism of toxicity contributes to understanding how CNS damage is spread even in the current ART era and how minimal or controlled HIV infection still results in cognitive impairment in a large population of infected individuals.

HIV-Associated Lung Infections and Complications in the Era of Combination Antiretroviral Therapy

The spectrum of lung diseases associated with HIV is broad, and many infectious and noninfectious complications of HIV infection have been recognized. The nature and prevalence of lung complications have not been fully characterized since the Pulmonary Complications of HIV Infection Study more than 15 years ago, before antiretroviral therapy (ART) increased life expectancy. Our understanding of the global epidemiology of these diseases in the current ART era is limited, and the mechanisms for the increases in the noninfectious conditions, in particular, are not well understood. The Longitudinal Studies of HIV-Associated Lung Infections and Complications (Lung HIV) Study (ClinicalTrials.gov number NCT00933595) is a collaborative multi-R01 consortium of research projects established by the National Heart, Lung, and Blood Institute to examine a diverse range of infectious and noninfectious pulmonary diseases in HIV-infected persons. This article reviews our current state of knowledge of the impact of HIV on lung health and the development of pulmonary diseases, and highlights ongoing research within the Lung HIV Study.

Pulmonary function abnormalities in HIV-infected patients during the current antiretroviral therapy era.

Before the introduction of combination antiretroviral (ARV) therapy, patients infected with HIV had an increased prevalence of respiratory symptoms and lung function abnormalities. The prevalence and exact phenotype of pulmonary abnormalities in the current era are unknown. In addition, these abnormalities may be underdiagnosed. Our objective was to determine the current burden of respiratory symptoms, pulmonary function abnormalities, and associated risk factors in individuals infected with HIV. Cross-sectional analysis of 167 participants infected with HIV who underwent pulmonary function testing. Respiratory symptoms were present in 47.3% of participants and associated with intravenous drug use (odds ratio [OR] 3.64; 95% confidence interval [CI], 1.32-10.046; P = 0.01). Only 15% had previous pulmonary testing. Pulmonary function abnormalities were common with 64.1% of participants having diffusion impairment and 21% having irreversible airway obstruction. Diffusion impairment was independently associated with ever smoking (OR 2.46; 95% CI, 1.16-5.21; P = 0.02) and Pneumocystis pneumonia prophylaxis (OR 2.94; 95% CI, 1.10-7.86; P = 0.01), whereas irreversible airway obstruction was independently associated with pack-years smoked (OR 1.03 per pack-year; 95% CI, 1.01-1.05; P < 0.01), intravenous drug use (OR 2.87; 95% CI, 1.15-7.09; P = 0.02), and the use of ARV therapy (OR 6.22; 95% CI, 1.19-32.43; P = 0.03). Respiratory symptoms and pulmonary function abnormalities remain common in individuals infected with HIV. Smoking and intravenous drug use are still important risk factors for pulmonary abnormalities, but ARV may be a novel risk factor for irreversible airway obstruction. Obstructive lung disease is likely underdiagnosed in this population.

The ART of caring for patients with HIV infection in the ICU

The ART of caring for patients with HIV infection in the ICU

Cerebrospinal Fluid Proteomics Reveals Potential Pathogenic Changes in the Brains of SIV-Infected Monkeys

The HIV-1-associated neurocognitive disorder occurs in approximately one-third of infected individuals. It has persisted in the current era of antiretroviral therapy, and its study is complicated by the lack of biomarkers for this condition. Since the cerebrospinal fluid is the most proximal biofluid to the site of pathology, we studied the cerebrospinal fluid in a nonhuman primate model for HIV-1-associated neurocognitive disorder. Here we present a simple and efficient liquid chromatography-coupled mass spectrometry-based proteomics approach that utilizes small amounts of cerebrospinal fluid. First, we demonstrate the validity of the methodology using human cerebrospinal fluid. Next, using the simian immunodeficiency virus-infected monkey model, we show its efficacy in identifying proteins such as alpha-1-antitrypsin, complement C3, hemopexin, IgM heavy chain, and plasminogen, whose increased expression is linked to disease. Finally, we find that the increase in cerebrospinal fluid proteins is linked to increased expression of their genes in the brain parenchyma, revealing that the cerebrospinal fluid alterations identified reflect changes in the brain itself and not merely leakage of the blood-brain or blood-cerebrospinal fluid barriers. This study reveals new central nervous system alterations in lentivirus-induced neurological disease, and this technique can be applied to other systems in which limited amounts of biofluids can be obtained.

Survival for Patients With HIV Admitted to the ICU Continues to Improve in the Current Era of Combination Antiretroviral Therapy

The combination antiretroviral therapy (ART) era (1996 to the present) has been associated with improved survival among HIV-infected outpatients, but ICU data from 2000 to the present are limited. We conducted a retrospective study of HIV-infected adults who had been admitted to the ICU at San Francisco General Hospital (from 2000 to 2004). The primary outcome was survival to hospital discharge. During the 5-year study period, there were 311 ICU admissions for 281 patients. Respiratory failure remained the most common indication for ICU admission (42% overall), but the proportion of patients with respiratory failure decreased each year from 52 to 34% (p = 0.02). Hospital survival ratios significantly increased during the 5-year period (p = 0.001). ART use at ICU admission was not associated with survival, but it was associated with higher CD4 cell counts, lower plasma HIV RNA levels, higher serum albumin levels, and lower proportions with AIDS-associated ICU admission diagnoses and with Pneumocystis pneumonia. In a multivariate analysis, a higher serum albumin level (adjusted odds ratio [AOR], 2.08; 95% confidence interval [CI], 1.41 to 3.06; p = 0.002) and the absence of mechanical ventilation (AOR, 6.11; 95% CI, 2.73 to 13.72; p < 0.001) were associated with survival. In this sixth in a series of consecutive studies started in 1981, we found that the epidemiology of ICU admission diagnoses continues to change. Our study also found that survival for critically ill HIV-infected patients continues to improve in the current era of ART. Although ART use was not associated with survival, it was associated with predictors that were associated with survival in a multivariate analysis.

Prevalence of HIV-related Pulmonary Arterial Hypertension in the Current Antiretroviral Therapy Era

Prevalence of HIV-related Pulmonary Arterial Hypertension in the Current Antiretroviral Therapy Era

Prevalence of HIV-related Pulmonary Arterial Hypertension in the Current Antiretroviral Therapy Era

Prevalence of HIV-related Pulmonary Arterial Hypertension in the Current Antiretroviral Therapy Era

Prevalence of HIV-related Pulmonary Arterial Hypertension in the Current Antiretroviral Therapy Era

The prevalence of HIV-associated pulmonary arterial hypertension (PAH) has not been evaluated since introduction of combined, highly active antiretroviral treatments. To establish the current prevalence of PAH in a large HIV-positive population. Prospective study conducted in 7,648 consecutive HIV-positive adults in 14 HIV clinics in France. PAH was identified through screening with a predefined algorithm. Patients with dyspnea unexplained by other causes underwent transthoracic Doppler echocardiography. PAH was suspected if peak velocity of tricuspid regurgitation was greater than 2.5 m/second and was confirmed by right heart catheterization. PAH was diagnosed if mean pulmonary arterial pressure at rest was 25 mm Hg or greater (with pulmonary capillary wedge pressure < or = 15 mm Hg) or 30 mm Hg or greater on exercise. A total of 739 patients had dyspnea, of which 312 met exclusion criteria and 150 refused to participate. Among the remaining 277, 30 had known PAH and 247 had unexplained dyspnea and underwent echocardiography; PAH was suspected in 18 and confirmed in 5, to give a total of 35 cases. The prevalence was thus 0.46% (95% confidence interval, 0.32-0.64%). All new cases had relatively milder PAH. The prevalence of HIV-associated PAH is about the same as it was in the early 1990s. Given the current good long-term prognosis of patients with HIV, the severity of PAH in HIV-infected patients, and the absence of predictive factors, careful screening for PAH is warranted for patients with unexplained dyspnea.