Interactions between opportunistic micro-organisms and HIV in the lung.

The lung is a major focus of disease in patients with acquired immunodeficiency syndrome (AIDS) and particular emphasis has always been placed upon the diagnosis and treatment of the opportunistic micro-organisms responsible for the severe and life threatening pneumonias. ' 2 Numerous prophylactic approaches for preventing and controlling these opportunistic pathogens have been published. Despite the implementation of these procedures the prognosis for patients with AIDS is poor with an average survival time from diagnosis to death of 17 months. ' As a result of the profound immunosuppression induced by HIV, pneumonias are common during the course of the disease, due to three major types of pathogens: Pneumocystis carinii, Mycobacterium tuberculosis, and pyogenic bacteria. Indeed, even with widespread prophylaxis Pneumocystis carinii remains the commonest opportunistic microorganism of the lung among patients with AIDS in the industrialised world.3 In subSaharan Africa and Asia the most common pulmonary complication in HIV infected individuals is tuberculosis.4 Coupled with the spread of multiple drug-resistant strains of tuberculosis amongst subjects with AIDS in the USA, tuberculosis threatens to spread into the general community. Furthermore, pyogenic bacterial infections are common in patients with AIDS and are an important cause of death in Africa.5 6The role of viral infections of the lung in HIV infected individuals, particularly those due to cytomegalovirus, remains controversial. Various mechanisms exist in which immune responses mounted by the host during pneumonia may modify the growth of HIV. These interactions between HIV and infectious agents in the lung may be harmful for the lung itself, and quite probably enhance the progression of the HIV disease in general.7 As HIV replicates best in activated or differentiated cells of the immune system, co-infections of these cells with opportunistic micro-organisms and HIV could enhance viral replication. Alternatively, cells releasing cytokines in response to a pathogen could trigger HIV replication in adjacent cells through a paracrine process. The high frequency of detection of HIV proviral DNA in alveolar lymphocytes and alveolar macrophages from patients with AIDS7 8 indicates that there is ample opportunity for interaction between opportunistic microorganisms and HIV in the lung. Depletion of CD4 + T lymphocytes and subsequent abrogation of the immune system by HIV greatly facilitates the development of Pneumocystis carinii pneumonia and onset of AIDS. However, P carinii pneumonia does not predispose alveolar lymphocytes or macrophages to infection in vivo and, conversely, although P carinii pneumonia is a marker for AIDS, HIV-1 infection of alveolar lymphocytes and macrophages is not a prerequisite for P carinii pneumonia.9 However, P carinii does significantly increase the recovery of HIV-1 from these cells,'01' and there is a fourfold increase in the number of HIV virions detectable in the cell free fluid obtained by bronchoalveolar lavage from individuals with P carinii pneumonia. 2 The cellular mechanisms underlying this phenomenon remain unclear, although increased levels of tumour necrosis factor x (TNFa) are secreted by the immunocompetent host in response to P carinii pneumonia. " Likewise, high levels ofTNFa are released by alveolar macrophages in the lung of HIV-1 infected individuals,4 " particularly during P carinii pneumonia. '6 Interestingly, increased production ofTNFa by alveolar macrophages does not correlate with an increase in the number of cells infected with HIV. 7 Furthermore, TNFa has been shown to be a potent stimulator of HIV-1 replication'8 and thus could offer a mechanism by which significant replication of HIV may occur in the lung. Conversely, in vitro experiments on HIV infected macrophages exposed to P carinii show that they release less TNFa than uninfected cells. "' An early effect of infection with HIV-1 is the reactivation of previously dormant tubercle bacilli. One consequence of interaction between Mycobacterium tuberculosis and HIV is a decreased control of both infections by host cells. An important action of HIV is inhibition of T lymphocyte mediated immune functions that maintain mycobacterial dormancy.20 Both CD4 and CD8 T lymphocyte functions are essential for protection against M tuberculosis. Even a moderate reduction in the number of CD4 T lymphocytes is sufficient to enable reactivation of tuberculosis.2' Furthermore, peripheral blood mononuclear cells from HIV infected subjects with tuberculosis have decreased proliferative and type 1 responses on stimulation with M tuberculosis.22 Consequently, blood monocytes from patients with tuberculosis are more susceptible to the growth of HIV.2 The phagocytosis ofM tuberculosis by monocyte cell lines enhances the replication of HIV-1 and HIV-2 in these cell lines24 25 but, surprisingly, whilst virus transcription is increased, release of infectious virus from the cells is reduced. This scenario may facilitate the spread of HIV by 875