Potential role of alveolar macrophages in HIV persistence and lung disease

While antiretroviral therapy (ART) has revolutionized the management of human immunodeficiency virus (HIV) and has enabled people living with HIV (PLWH) to achieve near-normal life expectancy, an HIV cure remains elusive due to the presence of HIV reservoirs. Furthermore, compared with individuals in the general population, PLWH experience a higher burden of multimorbidity, including both infectious and non-infectious pulmonary diseases, which may be a consequence of the formation of HIV reservoirs. In PLWH, the gut, lymph nodes, brain, testes, and lungs constitute important anatomical reservoirs of HIV. While CD4⁺ T-cells, and particularly memory CD4⁺ T-cells, are the best characterized cellular HIV reservoirs, tissue resident macrophages (TRM) and alveolar macrophages (AM) also harbor the virus. AMs are the most abundant cells in the bronchoalveolar (BAL) fluid in healthy individuals, and act as sentinels in the alveolar space, patrolling and clearing debris, microbes, and recycling surfactants. Embryonic-origin AMs residing in long-lived tissues have the capacity to self-renew without replenishment from peripheral monocytes. As with other tissues, close cell-to-cell contact in the lungs also provides a conducive environment for the cell-to-cell spread of HIV infection and the establishment of reservoirs. Since the lungs are constantly exposed to antigens from the external environment, this situation contributes to a pro-inflammatory phenotype rendering pulmonary immune cells exhausted and senescent—an environment that facilitates HIV persistence. Factors such as smoking, e-cigarette use, lung microbiome dysbiosis, and respiratory coinfections further drive antigenic stimulation and HIV replication. HIV replication, in turn, contributes to ongoing inflammation and clonal expansion. This article discusses the potential role of AMs in HIV persistence and their contribution to pulmonary inflammation and immune dysregulation, which may in turn render PLWH susceptible to chronic lung disease, despite ART. Finally, strategies to eliminate HIV-infected AMs are discussed.