The Complexity of HIV Persistence and Pathogenesis in the Lung Under Antiretroviral Therapy: Challenges Beyond AIDS

Abstract

Antiretroviral therapy (ART) represents a significant milestone in the battle against AIDS. However, we continue learning about HIV and confronting challenges 30 years after its discovery. HIV has cleverly tricked both the host immune system and ART. First, 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 introduced. Second, even under the suppressive pressures of ART, HIV still increases inflammatory mediators, deregulates apoptosis and proliferation, and induces oxidative stress in the host. Third, the preference of HIV for CXCR4 as a co-receptor may also have noxious outcomes, including potential malignancies. Furthermore, HIV still replicates cryptically in anatomical reservoirs, including the lung. HIV impairs bronchoalveolar T-lymphocyte and macrophage immune responses, rendering the lung susceptible to comorbidities. In addition, HIV-infected individuals are significantly more susceptible to long-term HIV-associated complications. This review focuses on chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension, and lung cancer. Almost two decades after the advent of highly active ART, we now know that HIV-infected individuals on ART live as long as the uninfected population. Fortunately, its availability is rapidly increasing in low- and middle-income countries. Nevertheless, ART is not risk-free: the developed world is facing issues with antiretroviral drug toxicity, resistance, and drug-drug interactions, while developing countries are confronting issues with immune reconstitution inflammatory syndrome. Several aspects of the complexity of HIV persistence and challenges with ART are discussed, as well as suggestions for new avenues of research.

Lung cancer in persons with HIV

“…The lung may serve as a compartment where HIV activity may not reflect systemic viral suppression[34]. This theory is supported by recent work from Cribbs et al showing that 70% of a cohort of 23 HIV infected non-smokers with ART-mediated viral suppression had measurable proviral DNA in alveolar macrophages[35].…”

Lung function abnormalities in HIV‐infected adults and children

“…While the association between risk factors for obstructive lung disease like tobacco and inhalational drug use and recurrent opportunistic infections suggests an increased susceptibility to the deleterious effects of inhaled noxious particles and pulmonary infection, the observed association with ART is unexplained. Potential mechanisms include direct drug effects (ART has been shown to increase oxidative stress in the lung), or aberrant immune restoration and chronic airway inflammation in response to persistent viral, bacterial or fungal antigens (analogous to the immune reconstitution inflammatory syndrome observed secondary to other pulmonary pathogens) . This association between airflow obstruction and ART has not been uniformly observed, however: for example, a cohort of 98 HIV‐infected patients from Philadelphia (mean age 44.8, 84% male, 55% smokers) with a prevalence of obstructive spirometry of 13.6% found that airflow obstruction was associated with increased age, greater number of pack‐years smoked and previous Pneumocystis infection, but not ART use …”

The effect of HIV infection and HCV viremia on inflammatory mediators and hepatic injury—The Women’s Interagency HIV Study

“…Liver fibrosis, as measured by a high APRI or FIB-4 score, was associated with an increase in a number of inflammatory mediators including sICAM, sVCAM and IP-10 in women with chronic hepatitis C (HCV RNA+) compared to HCV RNA- women. One chemokine in particular, IP-10, an interferon-induced protein that has been implicated in liver fibrosis [ 34 , 35 ] and lower ability to clear infection [ 36 ], was elevated in HCV RNA+ women even among those women with suppressed HIV replication (elite controllers and ART responders). The very high IP-10 levels seen in the women with uncontrolled HIV replication dominate the relatively weaker IP-10 induction driven by HCV RNA.…”