Jose Luis Sandoval Gutierrez1 , Sharilyn Almodovar2
1)Instituto Nacional de Enfermedades Respiratorias Ismael Coslo Villegas,Mexico City, Mexico
2)University of Colorado Anschutz Medical Campus,Pulmonary Sciences and Cricial Care Medicine,Aurora, Colorado, USA
Infection with human immunodeficiency virus (HIV) is now a chronic disease, thanks to the unquestioned success of antiretroviral therapies. Nevertheless, patients, clinicians and researchers are still facing challenges thirty years after the discovery of the virus. HIV has cleverly tricked both the host immune system and antiretroviral therapy (ART). As a first instance, the many HIV subtypes and recombinant forms have different susceptibilities to antiretroviral drugs, which may represent an issue in countries where ART is just being made available. Second, even under ART-induced viral suppression, HIV still promotes inflammation, deregulates bystander cell biology, and induces oxidative stress in the host. Third, the preference of HIV for CXCR4 as co-receptor may also have noxious outcomes including potential malignancies. Furthermore, HIV still replicates cryptically in anatomical reservoirs like the lung and impairs bronchoalveolar cell immune responses, rendering the lung susceptible to co-morbidities. Hence, it is becoming evident that HIV-infected individuals are significantly more susceptible to long-term HIV-associated complications, particularly now that HIV-infected individuals on ART live as long as the uninfected population. With this review, we will focus on chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension and lung cancer to hopefully braid concepts, give good starting points, and food for thought to pulmonologists, HIV specialists, cardiologists, and the new generations of scientists to jump-start new efforts towards HIV-associated pulmonary diseases as common goal.
Our respiratory tract is exposed to a myriad of everything from gases, dusts, pollens, oxidants, gastric contents, live pathogenic and non-pathogenic bacteria, fungi, and viruses. Together, these represent relentless challenges to the respiratory immune system, which relies in physical aerodynamic and immune barriers to maintain the lungs in good health; this would ensure an undisturbed gas exchange process, which is the ultimate physiologic goal of the lung. In addition, systemic diseases like infection with human immunodeficiency virus (HIV) may affect the lung. This colloquial review will focus on the impact of HIV in pulmonary immunology and the new challenges in both developed and developing countries, focusing on the non-infectious complications of HIV disease.
Human immunodeficiency virus: a constant challenge
HIV causes AIDS: that’s not new; it has been the topic of intense research efforts all over the world for over 30 years now. HIV produces billions of virions per day and has a rapid turnover with new generations every 2.6 days . Due to its extensive genetic variability, the main group of HIV type 1 is subtyped into nine genetic variants (A, B, C, D, F, G, H, J, and K), all of which recombine, which in turn introduce differences in mutation rates and fitness.
Understanding HIV interactions with the host is essential to learn about the viral strategies to induce pathogenicity and to identify potential additional therapeutic targets. Let’s start a discussion of key concepts on HIV entry, persistence and pathogenesis.
HIV receptors. HIV enters the cells via interactions with CD4 receptor in the host cell and C-C chemokine receptor-5 (CCR5) and C-X-C chemokine receptor-4 (CXCR4). The CCR5 is a receptor for RANTES/CCL5, MIP-α/CCL3, and MIP-β/CCL4 in primary macrophages . The CCR5 receptor is expressed in microglia, T lymphocytes, macrophages and dendritic cells (DC). On the other hand, CXCR4 is a 7-transmembrane G protein-coupled receptor used by HIV as co-receptor for preferential entry to T cells lines . Its natural ligand is stromal derived factor-1 (SDF-1/CXCL12)  Conventionally, HIV virions that use CCR5 as portal of entry are designated as “R5”, while virions using CXCR4 are referred to as “X4”. The HIV preference for CCR5 co-receptor switches to a preference for CXCR4 over the course of HIV infection; this co-receptor switch predicts progression to AIDS in ~50% of HIV+ individuals .
HIV-mediated evasion of immune surveillance. HIV hides in cells by downregulation of key host receptors to evade immune surveillance . For example, HIV-Nef is a key player in HIV pathogenesis by enhancing infectivity and downregulating critical molecules such as major histocompatibility complex-1 (MHC-1) and CD4 receptors . It is known that Nef downregulates the CD4 receptor by targeting it to the endocytic degradation pathway in clathrin-coated vesicles. CD4 downregulation stimulates viral replication in primary T cells . HIV Nef also downregulates MHC-1 by sequestering it in the trans-Golgi and hence, it prevents the recycling of this receptor from the Golgi to the membrane. Nef has highly conserved protein-protein interaction domains essential for these functions . In addition, the Nef signature motifs used to downregulate MHC-1 are also used to downregulate CXCR4 and CCR5 which decreases the chances of HIV superinfection [10, 11] and the SOS call to the immune system.
HIV Hiding Places: Reservoirs. HIV-infected individuals who are compliant to antiretroviral therapy (ART) show an apparent clearance of the virus in the peripheral blood shortly after initiating therapy. Nevertheless, viral particles can be detected after interruption of antiretrovirals [12-14] and there is genetic HIV evolution over time in patients with undetectable viremia, suggesting a continuous low level replication of HIV even below the limits of clinical detection. This notion has been supported by the finding that in the presence of suppressive ART, the integrated HIV (AKA. archival, proviral HIV) and extrachromosomal HIV (episomal, surrogate for recent infection) belong to different viral populations .
Where does the virus hide? Resting T lymphocytes (memory cells) or long-lived myeloid cells (macrophages and DC) remain transcriptionally silent for long periods of time while having integrated copies of the HIV genome, especially in the presence of antiretroviral therapy [16-19]. The activation of these cells resumes the production of infectious particles and hence, the story repeats all over again by infection of new cells ó reseeding of the reservoir ó return to resting state and perpetuation of the persistence of HIV. At the organ/system level, anatomic compartments that may serve as reservoirs of HIV include the central nervous system [20, 21], the genitourinary tract [22, 23], and the gut-associated lymphoid tissue [24, 25].
The pulmonary microenvironment can also embrace high levels of HIV replication . In the alveoli, lymphocytes are more susceptible to HIV infection than macrophages. HIV infects 1 in 100 of CD4+ alveolar lymphocytes  and 1 in 1,000 alveolar macrophages (AM) . The alveolar space harbors small and large sub-populations of macrophages, which differ not only in morphology but also in cell surface markers [31, 32]. HIV preferentially infects the small macrophages, which exhibit more of highly active inflammatory phenotypes .
May the lungs act as anatomical reservoirs for HIV? Studies in the 90’s showed significantly complete phylogenetic separation of the HIV lineages in the lung, blood, brain and testis . A decade later, studies that compared HIV env sequences spanning the second constant and the fifth variable region (C2-V5) from matched blood and lung samples (either lung sputa or BALc) found lung-specific evolution in up to 56% of HIV-infected individuals .
The existence of HIV reservoirs demonstrates that ART does not eliminate from the host. Although evidence points to lung-specific viral evolution, the lung is not as anatomically enclosed as the brain and hence, viruses circulate freely aided by the active blood flow through the cardiopulmonary system. In light of this, it is clear that HIV may contribute to immune disturbances leading to pulmonary complications.
HIV as an intrapulmonary pathogen:
While some studies suggest that alveolar macrophages are resilient to HIV infection and remain competent to respond to Streptococcus pneumoniae [37, 38] and Cryptococcus neoformans , others suggest that HIV alters the pulmonary cell biology to the point that compared to HIV-uninfected counterparts, HIV-infected individuals have lower secretion of IFN-γ and tumor necrosis factor-alpha (TNF-α) in the lung, significantly increased RANTES and lysozyme in the BALf , marked cellular activation and accumulation of inflammatory mediators in the alveolar space, including increased HIV-specific CD8+ T cells. All these get complicated by smoking, which certainly complicates the immunologic landscape in the lungs , .
The presence of HIV in the lungs also impacts bystander pulmonary resident cells like endothelial cells. Although pulmonary endothelial cells are resistant to HIV infection , EC remain susceptible to apoptosis when exposed to HIV proteins [43-46] suggestion that while EC may not represent a cellular source of HIV in the lung, they certainly remain susceptible to the cytopathic effects of HIV that may eventually lead to HIV-associated pulmonary complications including chronic obstructive pulmonary disease (COPD), lung cancer, pulmonary arterial hypertension (PAH), fibrosis and infections [47, 48]. For instance, COPD is characterized by limited expiratory airflow, affecting individuals from 45 to 52 years of age , is the third leading cause of mortality in the world, and a significant risk factor for hospitalizations in the HIV-infected population [51-53] regardless of smoking status and antiretroviral therapy [51, 54], and in association with inflammatory markers [55, 56], increased oxidative stress  Of note, contrasting studies reported that there is not a significant risk for COPD (odds ratio (OR)= 1.61) or lung cancer (OR= 2.65) in HIV-infected individuals, particularly in the era post-antiretrovirals . However, it is very likely that the reported findings were masked by the presence of unrecognized COPD because that study relied on self-reported pulmonary diagnoses, which were not clinically confirmed. Together, this suggests that the presence of infectious pathogens like HIV, coupled with abnormal inflammatory responses and oxidative stress all contribute mechanistically to HIV-COPD.
Emphysema is a form of COPD characterized by apoptosis of epithelial and alveolar cells, with various degrees of inflammation. While cigarette smoking is a major cause of COPD/emphysema , HIV is another risk factor for COPD, regardless of smoking status. Histologically, HIV is mostly found in the emphysematous regions of the lung, while very rare HIV+ cells are present in normal lung areas , suggesting a direct role of HIV and/or HIV proteins in emphysema. One of the mechanistic insights offered for the lung endothelial cell apoptosis is the upregulation of the inflammatory cytokine endothelial monocyte activating polypeptide II (EMAP II)  and that such upregulation is induced by gp120 signaling through the CXCR4 receptor and activation of p38 MAPK .
Relevant to chronic bronchitis, CXCR4 and HIV-X4 viruses are implicated in the overproduction of mucus and mucous cell metaplasia in human bronchial epithelial cells in vitro, via the CXCR4/α7-nicotinic acetylcholine receptor/ γ-aminobutyric acid (GABA)-A receptor axis . These results further support a potential role of HIV in higher incidence of COPD.
2) Pulmonary arterial hypertension is a rare disease in the general population, affecting 1-2 persons per million individuals but is significantly more frequent in the HIV-infected population, regardless of gender, age, socio-demographic characteristics, duration of HIV diagnosis, and interventions with ART.
Listed in the Group 1 of clinical classification of the 5th World Symposium of Pulmonary Hypertension  HIV-associated PAH is characterized by increased inflammatory cytokines, atypical pulmonary vascular remodeling featured quasi-malignant phenotype of pulmonary endothelial cells [64, 65], and highly glycolytic pulmonary artery vascular cells [66, 67]. In addition, a signature of PAH is the presence of cells that obliterate the lumina of pulmonary arteries (plexiform lesions) ; therefore, the mean pulmonary artery pressures increase (mPAP >25 mmHg), ending fatally due to right heart failure. PAH can be screened by echocardiography, which measures PASP and diagnosed by right heart catheterization (RHC), which measures mPAP; final diagnosis is made based on mPAP > 25 mm Hg, pulmonary arteriolar wedge pressure <15 mmHg and pulmonary vascular resistance > 3 Wood units. Clinically, HIV-PAH presents as any idiopathic PAH. Symptoms are often nonspecific and insidious, so they are attributed to other complications of HIV or HIV itself. The time of presentation to the diagnosis is often long, from 6 to 2 years, or many times it is just overlooked.
The prevalence of PAH in HIV-infected population is usually reported to be 1 in 200 (0.5%) individuals. Nonetheless, the awareness of HIV-PAH has increased in medical communities worldwide, as evidenced by the coordination of taskforces aimed to screen patients who are asymptomatic for pulmonary arterial hypertension. PAH has been recently reported to affect 0.2-12.7% of HIV-infected individuals in several countries, based on either echocardiographic PASP or RHC. Based on these results, and the fact that PAH screening and diagnostic tools are not part of the routine clinical care to HIV-infected individuals, there are two questions on the table: should all patients with PAH should undergo HIV testing ? or should all patients with HIV undergo screening for PAH?
A study comparing pressures measured by Doppler-based echocardiography vs right heart catheterization showed that 19.7% of the Doppler-based measurements were inaccurate, missing the PAH phenotype in 1/3 patients  Despite this, the reality is that many patients may just decline the RHC procedure, are ineligible or it may just not be available, especially in low-resource settings. Hence, the best scenario in many instances is to retrieve echocardiography data and use PASP 30-35 mm Hg as a cutoff for echocardiographic abnormalities associated with PAH, with the caveat that some of these data may still be underestimated but at least, accounted for.
The increased prevalence of HIV-PAH (whether accurate or undestimated) has been documented by several studies worldwide but, do we have new ideas about new mechanisms and targets for therapy? Do we really know what in HIV increases the chances of PAH? There is no definitive proof that HIV causes PAH and no evidence that HIV infects lung endothelial cells57. However, viral proteins and their interactions with molecular partners in the infected cells may damage endothelial cells, induce inflammation and deregulate apoptosis and proliferation of vascular endothelial cells in the lung, resulting in pulmonary vascular remodeling featured in PAH patients [44, 45, 72-74]. Primate models recapitulate intimal and medial hyperplasia along with elevated pulmonary pressures associated with human PAH, as reported after infection of the animals with chimeric SHIVenv virions . Additional HIV proteins like Nef co-localizes with EC in PAH-like plexiform lesions and promotes severe dysfunction of the Golgi tethers at the sub-cellular level [76-78]. Additional studies found Nef signature sequences associated with the PAH phenotype in humans . Together, these studies suggest that HIV proteins play key roles in the pathogenesis of HIV-PAH.
The combination of HIV –and/or its proteins- and recreational drugs like cocaine exacerbates pulmonary arteriopathies. For example, HIV Tat and cocaine disrupts tight junction proteins, increases the expression of platelet-derived growth factor and increases the proliferation of pulmonary smooth muscle cells particularly when Tat and cocaine are combined. Moreover, macaques exposed to the simian immunodeficiency virus (simian homologue of HIV) and morphine exhibit significant pulmonary vascular remodeling and oxidative-stress mediated apoptosis of endothelial cells followed by proliferation of apoptosis-resistant cells .
3) HIV-associated malignancies that define AIDS (e.g. Kaposi's sarcoma, non-Hodgkin lymphoma, and cervical cancer) have decreased in the post-ART era; nonetheless, the incidence of non-AIDS –defining cancers (NADC) have tripled: lung cancer is now the leading cause of NADC. Up to 52% of deaths in the post-ART era have been ascribed to NADC, including liver, gastric, colorectal and lung malignancies, which occurred in patients with fairly well-controlled HIV disease [82-84].
The most common type of lung cancer in the HIV-infected population is the adenocarcinoma , although non–small cell lung cancer (NSCLC) was found in 88% of cases with HIV-associated lung cancer . Compared to the HIV-uninfected population, patients with HIV present with a younger age (mean 50 years) at the time of diagnosis with lung cancer . In addition, most of the affected patients are smokers and unfortunately, present with symptoms of advanced cancer . HIV itself is an independent risk factor for lung cancer, regardless of smoking, COPD and bacterial pneumonia .
One of the mechanisms proposed for HIV-associated lung cancer is immunosuppression [83, 84, 89]. Separate studies found a 2.2 relative risk of lung cancer in HIV-infected immunosuppressed patients (with CD4 counts <200 cells/mL), compared to uninfected . Contrasting data from several groups show that lung cancer in HIV-infected individuals is not associated with CD4 counts [91-93], despite the inverse relationship with HIV viral load .
Additional mechanistic views into lung malignancies associated with HIV infection are provided by respiratory infections and genomic instability. The HIV-infected population is particularly prone to bacterial pneumonia, in addition to mycobacterial Pneumocystis, and viral respiratory infections. Pulmonary infections, in turn, may increase the risk of lung malignancies in the HIV-infected population [91, 95, 96]. In addition, genomic instability, reflected by microsatellite alterations, has been hypothesized to increase the risk of lung cancer in HIV. Microsatellite alterations, but not the loss of heterozygosity, were significantly increased (6-fold higher) in HV-associated lung carcinomas . What produces this HIV-related genomic instability? A previously unrecognized interaction between HIV and endogenous retrotransposable elements has been uncovered with the finding that HIV infection results in accumulation of Type 1 long-interspersed nuclear elements (L1s) DNA in primary CD4+ lymphocytes .
Inflammation is also an ingredient in the recipe for HIV-associated cancers. A study that evaluated activated inflammatory pathways (IL-6 and C-reactive protein) and coagulation pathways (D-dimer) in HIV-infected patients found that individuals with higher levels of IL-6 had significantly higher risk for cancer .
Despite the potential underestimations due calculations based on self-reported disorders, the use of screening tools for diagnosis or even undocumented patient cohorts, the higher susceptibility of HIV+ patients to serious lung complications including COPD, PAH and lung cancers is evident. Inflammation, oxidative stress, de-regulated apoptosis and proliferation, and malignant phenotypes are common denominators in the quest for mechanistic hints. Many of the specifics regarding the direct and indirect role of the virus in these diseases remain undetermined.
We have won many battles against HIV/ADS aided by antiretrovirals but not the war. We are still learning about the HIV molecular tricks and facing challenges thirty years after its discovery. This review presents key concepts of HIV persistence and focused on how the lung resents HIV, echoing to HIV-associated pulmonary complications like COPD, pulmonary arterial hypertension and lung malignancies.
We still need systematic epidemiological surveillance to document HIV-associated pulmonary complications globally; therefore, we insist that the crosstalk between pulmonologists, cardiologists, and HIV specialists is essential to document the true prevalence of these diseases, which otherwise would go unnoticed and untreated before the patient’s quality of life is seriously deteriorated.
Antiretroviral drug toxicity, resistance and drug-drug interactions are issues affecting both the developed and the developing world, which certainly require extensive research, pharmacological formulations, and implementation of revised therapeutic strategies.
New research enterprises are certainly warranted at the basic science level. For instance, the role of HIV and HIV-proteins in PAH, particularly at the sub-cellular level and the impact in cellular cross-talk (e.g. EC, macrophages, T cells, SMC) remain as opportunities to carve deeper niches to eventually identify novel therapeutic targets. In addition, it is necessary learn more about the modulation of cellular sources of viruses within reservoirs in order to strategize for a functional eradication of HIV reservoirs. Finally, the role of chronic inflammation in HIV-associated pulmonary diseases is certainly a unifying, hypothesis-generating topic that can take us to the next level.
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