Impact of antiretroviral therapy on lung immunology and inflammation.

In its 2010 report, the World Health Organization estimates that 34 million people worldwide are living with HIV 1 Lung disease is a major source of morbidity and mortality in these patients and can be directly linked to progressive loss of pulmonary immunity. Typically, infections complications occur in an orderly fashion, with increased susceptibility to common pathogens occurring early in HIV infection and susceptibility to opportunistic pathogens appearing later after substantial losses of CD4+ T cells (Figure 1). The immunologic correlate of this progression is the loss of antigen-specific immune responses early in HIV infection, followed by the loss of alloantigen and finally mitogen responses. However, the development of combination antiretroviral therapy (ART) has greatly influenced the morbidity and mortality of HIV infection. This influence has generally been attributed to improvements in immunologic function, either by preventing the progressive loss of immunity in HIV infection or by actually promoting immune reconstitution. While the effects of ART are well described in the vascular compartment, their effects at the tissue level, including the lung, are just beginning to be understood. In this review, we will describe how ART has greatly improved the lung immunologic and inflammatory milieu in HIV-infected subjects. The consequences of this improvement will be discussed extensively by other authors contributing to this publication. 1 Progression of cellular immunodeficiency in HIV infection. There is early loss of antigen-specific immune responses and increased susceptibility to bacterial infections. Over time, there is progressive CD4+ T cell depletion, progressive loss of T cell ... Effect of HIV on Pulmonary Immune Responses The respiratory tract from the oropharynx to the alveoli serves as an interface between the host and the environment. Thus, pulmonary immune responses are felt to represent a form of mucosal immunity. Pulmonary immunity can be divided into innate and acquired responses. Most pathogens gaining access to the respiratory tract are phagocytized by alveolar macrophages (AM), the principal arm of innate immunity. Importantly, phagocytosis of most foreign material gaining access to the alveolar space does not result in an inflammatory response due to the general immunosuppressive properties of alveolar macrophages 2. This results in a generalized paucity of lung inflammation under normal conditions, allowing gas exchange to occur unimpeded. Failure of innate host defenses leads to persistence of antigen in the respiratory tract and initiation of specific acquired immune responses. This process, which typically occurs in regional lung lymphoid tissue, results in the production of antigen specific effector T and B cells which traffic back to the site of initial challenge, in this case the alveolar space, under the control of local chemokine production in the lung 3. During the initial antigenic response, memory B and T cells are also created that allow the host to respond more rapidly upon re-exposure to the same antigen. Importantly, memory cells make up the predominant resident lymphocyte population in the normal lung 4. HIV infection impacts all components of the pulmonary immune response and has been addressed in a prior chapter. Specifically, the alveolar environment in HIV infection is characterized by: Generalized alveolar macrophage activation 5,6. Generalized CD4 T cell and CD8 T cell activation 7,8. Preserved alveolar macrophage phagocytic function 6,9,10. Increased concentrations of most macrophage and lymphocyte cytokines studied to date 11. Mild decrease in absolute CD4 T cell counts and a large decrease in CD4:CD8 T cell ratio in the alveolar space 12,13. Early preferential loss of antigen-specific memory CD4 T cells 14-16. Increase in the number and percentage of CD8+ cells resulting in a lymphocytic alveolitis 17. High immunoglobulin concentrations 18,19, but poor opsonic activity 20,21. The end result of these changes is a generalized state of cellular activation and accumulation of immune cells and pro-inflammatory mediators in the alveolar space (Figure 2A). Since HIV is easily detectable in the lungs of HIV-infected individuals not on ART 22, it is reasonable to speculate that the virus itself can drive this response. In fact, very early studies recognized that HIV-infected individuals had an increase in lung CD8+ T cells consisting of HIV-specific cytotoxic T lymphocytes 17, a finding confirmed by later investigators 13. However, despite this apparent appropriate anti-HIV response and background “inflammatory” state, clearly defects in specific immunity are present as demonstrated by the increase in opportunistic infections. The challenge, and hope, of effective antiretroviral therapy is to return the alveolar compartment to a more “normal” state. 2 Effect of ART on the alveolar environment in HIV infection. A) In untreated patients, there is persistent HIV antigen in the lung leading to generalized cellular activation and augmented cytokine and chemokine secretion in response to pathogens and other ... Effects of ART on Pulmonary Immunity While there is extensive literature on effects of ART in controlling plasma viral load and improving immune responsiveness of peripheral blood mononuclear cells (PBMC), there is a paucity of data describing the effect of ART in tissue compartments, especially the lung. Much of the existing data on lung immunologic changes after starting ART pertain to IRIS which is a clinically recognized disease discussed later in this chapter. Less understood is the effect of ART on lung immune function and inflammation in individuals who are otherwise doing well after starting treatment. This type of analysis requires participation of HIV-infected individuals on ART in research protocols where studies such as bronchoscopy and chest imaging are performed in the absence of clinical symptoms. The existing literature on these types of studies is described here. A. Effects on lung HIV viral load If, as speculated above, the presence of HIV antigens in the lung drives the development of CD8+ lymphocytic alveolitis and induces generalized cellular activation in the pulmonary microenvironment, then control of the pulmonary viral load should return alveolar constituents towards a normal state. Thus, the first question to be addressed is whether ART can reduce the lung viral load. Cross-sectional studies had suggested that individuals on ART had decreased detection of HIV in BAL, compared with lavages obtained from individuals not on treatment 22. To address this question prospectively, a longitudinal study was conducted under the auspices of the Adult AIDS Clinical Trials Group in which blood and BAL were obtained from HIV-infected individuals starting ART and again after 4 weeks, and 24 weeks 23. At each time point, free virus (in plasma and acellular BAL fluid) as well as cellular HIV RNA and DNA (in PBMCs and alveolar cells) was measured. As expected, ART was associated with a significant decline in plasma viral load and a delayed, but significant decrease in the cellular viral load in peripheral blood cells. However, the decline in the lung viral load, both in the acellular compartment as well as in alveolar cells, was much more rapid and dramatic. At baseline, the ability to detect HIV in the lung and vascular compartments was similar. After four weeks of ART, the ability to detect HIV in BAL was significantly lower than the ability to detect HIV in plasma. After 6 months of therapy, the ability to detect HIV RNA in lung cells was significantly less than the ability to detect HIV RNA in PBMCs. Thus, the lung appears to respond to ART as well as, if not better, than the vascular compartment 23