A major barrier to human immunodeficiency virus (HIV-1) cure is the latent viral reservoir, which persists despite antiretroviral therapy (ART), including across the non-dividing myeloid reservoir which is found systemically in sanctuary sites across tissues and the central nervous system (CNS). Unlike activated CD4+ T cells that undergo rapid cell death during initial infection (due to rapid viral replication kinetics), viral replication kinetics are delayed in non-dividing myeloid cells, resulting in long-lived survival of infected macrophages and macrophage-like cells. Simultaneously, persistent inflammation in macrophages confers immune dysregulation that is a key driver of co-morbidities including cardiovascular disease (CVD) and neurological deficits in people living with HIV-1 (PLWH). Macrophage activation and dysregulation is also a key driver of disease progression across other viral infections including SARS-CoV-2, influenza, and chikungunya viruses, underscoring the interplay between macrophages and disease progression, pathogenesis, and comorbidity in the viral infection setting. This review discusses the role of macrophages in persistence and pathogenesis of HIV-1 and related comorbidities, SARS-CoV-2 and other viruses. A special focus is given to novel immunomodulatory targets for key events driving myeloid cell dysregulation and reservoir maintenance across a diverse array of viral infections.

B cell lymphoma 2 (BCL-2) family proteins are involved in the mitochondrial apoptotic pathway and are key modulators of cellular lifespan, which is dysregulated during human immunodeficiency virus type 1 (HIV-1) and other viral infections, thereby increasing the lifespan of cells harboring virus, including the latent HIV-1 reservoir. Long-lived cells harboring integrated HIV-1 DNA is a major barrier to eradication. Strategies reducing the lifespan of reservoir cells could significantly impact the field of cure research, while also providing insight into immunomodulatory strategies that can crosstalk to other viral infections. Venetoclax is a first-in-class orally bioavailable BCL-2 homology 3 (BH3) mimetic that recently received Food and Drug Administration (FDA) approval for treatment in myeloid and lymphocytic leukemia. Venetoclax has been recently investigated in HIV-1 and demonstrated anti-HIV-1 effects including a reduction in reservoir size. Another immunomodulatory strategy towards reduction in the lifespan of the reservoir is Jak 1/2 inhibition. The Jak STAT pathway has been implicated in BCL-2 and interleukin 10 (IL-10) expression, leading to a downstream effect of cellular senescence. Ruxolitinib and baricitinib are FDA-approved, orally bioavailable Jak 1/2 inhibitors that have been shown to indirectly decay the HIV-1 latent reservoir, and down-regulate markers of HIV-1 persistence, immune dysregulation and reservoir lifespan in vitro and ex vivo. Ruxolitinib recently demonstrated a significant decrease in BCL-2 expression in a human study of virally suppressed people living with HIV (PWH), and baricitinib recently received emergency use approval for the indication of coronavirus disease 2019 (COVID-19), underscoring their safety and efficacy in the viral infection setting. BCL-2 and Jak 1/2 inhibitors could be repurposed as immunomodulators for not only HIV-1 and COVID-19, but other viruses that upregulate BCL-2 anti-apoptotic proteins. This review examines potential routes for BCL-2 and Jak 1/2 inhibitors as immunomodulators for treatment and cure of HIV-1 and other viral infections.

Neurocognitive impairment (NCI) associated with HIV infection of the brain impacts a large proportion of people with HIV (PWH) regardless of antiretroviral therapy (ART). While the number of PWH and severe NCI has dropped considerably with the introduction of ART, the sole use of ART is not sufficient to prevent or arrest NCI in many PWH. As the HIV field continues to investigate cure strategies, adjunctive therapies are greatly needed. HIV imaging, cerebrospinal fluid, and pathological studies point to the presence of continual inflammation, and the presence of HIV RNA, DNA, and proteins in the brain despite ART. Clinical trials exploring potential adjunctive therapeutics for the treatment of HIV NCI over the last few decades have had limited success. Ideally, future research and development of novel compounds need to address both the HIV replication and neuroinflammation associated with HIV infection in the brain. Brain mononuclear phagocytes (MPs) are the primary instigators of inflammation and HIV protein expression; therefore, adjunctive treatments that act on MPs, such as immunomodulating agents, look promising. In this review, we will highlight recent developments of innovative therapies and discuss future approaches for HIV NCI treatment.

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