HIV-Related Lung Disorders

Abstract

Highly active antiretroviral therapy (HAART) has dramatically altered the spectrum of morbidity and mortality in HIV-infected patients. This has been attributed to improvements in the lung microenvironment leading to enhanced pulmonary immunity, either by preventing the progressive loss of immune function or by actually promoting immune restoration. However, these changes have been accompanied by the recognition of new pulmonary complications in HIV-infected subjects, especially those associated with immune reconstitution. In this review we will describe how HIV infection alters the normal pulmonary environment, highlight the effect of HAART on these perturbations, and discuss potential complications of HAART in the lung, focusing on the pulmonary immune reconstitution inflammatory syndrome.

Figure 1

Normal pulmonary immune responses. Antigen reaching the lower respiratory tract which is not cleared by phagocytosis is taken up, processed, and transported by accessory cells to regional lymphoid tissue. There antigen is presented to naïve CD4 T lymphocytes to form CD4 Th2 T cells for B cell help, CD4 Th1 delayed type hypersensitivity T cells, and CD8 cytotoxic T cells. These effector cells then traffic back to the site of initial challenge in the lung where they can undergo further expansion in situ.

Figure 2

Changes in the alveolar space with HIV progression. Over time there is a progressive loss of CD4 T cells (especially memory T cells leading to early loss of antigen-specific responses), loss of CD8+CD57- cytotoxic T lymphocyte (CTL), and an increase in CD8+ CD57+ cells with immune suppressive properties. As CD4 T cells and CD8 T cells decrease in late stage infection IFN-γ declines resulting in decreased phagocytic function and more advanced defects in acquired immunity.

Figure 3

Effect of HAART on the alveolar environment in HIV infection. 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 particulate antigens. This leads to further cellular activation and promotes influx of inflammatory cells to the alveolar space in a nonspecific manner, including B cells which are producing non-specific antibody. With HAART the pulmonary viral load decreases, reducing the antigenic load driving the nonspecific inflammatory pulmonary response. Less cellular activation is seen and nonspecific cytokine secretion resolves. Low level IFN-γ and IFN-γ inducible chemokine production continues leading to the normal trafficking of memory cells into the alveolar space rather than a massive influx of non-specific inflammatory cells.

Figure 4

Necessary requirements to develop immune reconstitution inflammatory syndrome. IRIS occurs when the CD4 count is increasing and viral RNA is decreasing, suggesting an adequate and appropriate response to HAART is a prerequisite. Other factors such as cytokine milieu and T cell subset redistribution are likely contributing factors. Most clinical cases of IRIS (bolded) occur early, within a few months of HAART initiation. However, there is clearly a window (shaded box) in which IRIS can occur “late” provided that an antigenic threshold is maintained (unrecognized opportunistic pathogen burden or unmasked autoantigens related to injury and T cell rebirth). Finally, if an individual has a genetic predisposition to a vigorous proinflammatory response to antigen after HAART initiation, IRIS may be early and fulminant.