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HIV-infected macrophage. Transmission electron microscopy picture of an HIV-infected macrophage taken by Dr. Mike Mashiba and Dr. Kathy Collins (University of Michigan).
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Although CD4+ T cells represent the major reservoir of persistent HIV and SIV infection, accumulating evidence suggests that macrophages also contribute. However, investigations of the role of macrophages are often underrepresented at HIV pathogenesis and cure meetings. This was the impetus for a scientific workshop dedicated to this area of study,...
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... support was generously provided by the Ragon Institute of MGH, MIT and Harvard. The authors would also like to thank and give photo credit for the image in Figure 1 to Dr. Kathy Collins and Dr. Mike Mashiba (University of Michigan) as well as Dr. David Collins in helping with the organization of the meeting and input with this review. ...
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Macrophages are key cells of the innate immune system with functional roles in both homeostatic maintenance of self-tissues and inflammatory responses to external stimuli, including infectious agents. Recent advances in metabolic research have revealed that macrophage functions rely upon coordinated metabolic programs to regulate gene expression, i...
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... As the infection progresses the count of CD4+ T cells drastically reduces, as CD4+ helper cells are key cells of the immune system leading to a weaker immune system. Along with the depletion of CD4+ helper T cells, the virus starts accumulating in the cellular structures which makes them undetected by the current Antiretroviral therapy (9). ...
... While bone marrow dendritic cells do not play an appreciable role in HSPC maintenance or haematopoiesis, selective ablation of dendritic cells results in increased HSPC mobilisation through an indirect mechanism involving CXCR2 (122). Dendritic cells and macrophages are capable of sustaining HIV replication and could contribute to viral dissemination in the niche (123)(124)(125). The perivascular niche is also home to megakaryocytes, which have been found to be susceptible to HIV infection both in vitro (126)(127)(128) and in vivo (128,129). ...
Dysregulation of the bone marrow niche resulting from the direct and indirect effects of HIV infection contributes to haematological abnormalities observed in HIV patients. The bone marrow niche is a complex, multicellular environment which functions primarily in the maintenance of haematopoietic stem/progenitor cells (HSPCs). These adult stem cells are responsible for replacing blood and immune cells over the course of a lifetime. Cells of the bone marrow niche support HSPCs and help to orchestrate the quiescence, self-renewal and differentiation of HSPCs through chemical and molecular signals and cell-cell interactions. This narrative review discusses the HIV-associated dysregulation of the bone marrow niche, as well as the susceptibility of HSPCs to infection by HIV.
... However, once the HAART is interrupted, the latent proviruses become activated and viral RNA is produced in the plasma up to the pre-treatment levels. Long-lived resting memory CD4+ T cells are the best-characterized cell type harboring the latent HIV-1, although monocytes and macrophages also contribute to the latent pool (Delobel et al., 2005;Gibellini et al., 2008;Clayton et al., 2017;Kruize and Kootstra, 2019). So far, cellular markers specific for the latently infected cells have not been identified, rendering the cure strategy extremely challenging. ...
Antiretroviral therapy can successfully suppress HIV-1 replication to undetectable levels but fails to eliminate latent and persistent HIV-1 reservoirs. Recent studies have focused on the immunomodulatory agents such as Toll-like receptor 7 and 8 (TLR7 and TLR8) capable of activating, thereby rendering the reservoir susceptible to antiretroviral inhibition and immune recognition and elimination. In this context, this study focused on generating a diverse repertoire of TLR7/8 agonists to identify more potent candidates for activating latent HIV-1 and immune cells’ response. Through combinational strategies of computer-aided design and biological characterization, 159 pyrido [3,2-d] pyrimidine and pyridine-2-amine-based derivatives were synthesized. Of which, two TLR7/8 dual and one TLR8-specific agonists with exceptionally high potency in activating HIV-1 latent reservoirs in cell lines and PBMCs of patients with persistent and durable virologic controls were identified. Particularly, these agonists appeared to enhance NK and T cells activity, which were correlated with the degree of surface activation markers. The outcome of this study highlights the remarkable potential of TLR7/8 agonists in simultaneously activating HIV-1 from the latently infected cells and augmenting immune effector cells.
... On the other hand, there is a mechanism that cannot be replicated, which is cell-to-cell contact. Not only does it provide co-stimulatory signals that are not present in the new experimental model, but also the cell-to-cell contact that allows the viral transfer from MDMs to CD4TLs [54]. CD4TLs are susceptible to HIV infection; so, there is an active cell-to-cell trans-infection process in the co-culture, which is absent when not using MDMs as activation stimulus. ...
In this study, we evaluate the role of the MIF/CD74 axis in the functionality of CD4+ T lymphocytes (CD4TL) during HIV infection. MDMs from healthy donors were infected with a R5-tropic or Transmitted/Founder (T/F) HIV strain. At day 11 post-MDM infection, allogeneic co-cultures with uninfected CD4TLs plus MIF stimulus were performed. Cytokine production was evaluated by ELISA. MIF plasma levels of people with HIV (PWH) were evaluated by ELISA. The phenotype and infection rate of CD4TLs from PWH were analyzed after MIF stimulus. Intracellular cytokines and transcription factors were evaluated by flow cytometry. Data were analyzed by parametric or non-parametric methods. The MIF stimulation of HIV-infected MDMs induced an increased expression of IL-6, IL-1β and IL-8. In CD4TL/MDM co-cultures, the MIF treatment increased IL-17A/RORγt-expressing CD4TLs. Higher concentrations of IL-17A in supernatants were also observed. These results were recapitulated using transmitted/founder (T/F) HIV-1 strains. The MIF treatment appeared to affect memory CD4TLs more than naïve CD4TLs. MIF blocking showed a negative impact on IL17A+CD4TL proportions. Higher MIF concentrations in PWH-derived plasma were correlated with higher IL-17A+CD4TL percentages. Finally, MIF stimulation in PWH-derived PBMCs led to an increase in Th17-like population. MIF may contribute to viral pathogenesis by generating a microenvironment enriched in activating mediators and Th17-like CD4TLs, which are known to be highly susceptible to HIV-1 infection and relevant to viral persistence. These observations establish a basis for considering MIF as a possible therapeutic target.
... Chronic inflammation is likely a result of macrophage dysregulation which can be more readily evaluated in rhesus macaques infected with SIV and treated with ART. And, although, CD4 + T lymphocytes serve as a primary target of infection, HIV and SIV are lentiviruses that also infect macrophages, especially as CD4 + T cells decline in numbers leaving macrophages more available for infection [3,[17][18][19][20][21][22][23]. These macrophage subpopulations appear to exhibit distinct functions during progressing stages of HIV/SIV infection [22,[24][25][26]. ...
Destruction of CD4+ T cells is a primary cause of immunodeficiency in Human Immunodeficiency Virus (HIV)-infected humans and Simian Immunodeficiency Virus (SIV)-infected rhesus macaques. Tissue macrophages, however, also contribute to AIDS pathogenesis. Studies on rhesus macaque lung revealed the presence of at least two types of macrophages comprising short-lived lung interstitial macrophages in the parenchyma that are not present in bronchoalveolar lavage (BAL), and the long-lived alveolar macrophages that predominate in BAL and rarely divide. Increased blood monocyte turnover was associated with death of infected short-lived tissue macrophages and terminal disease progression during AIDS. Antiretroviral therapy (ART) treatment of SIV-infected macaques effectively prevented active infection of short-lived macrophages in tissues and delayed disease progression. Interestingly however, longer-lived macrophages remained infected and survived despite ART. This suggests that the long-lived macrophages contribute to establishing a virus reservoir and that these infected persistent cells likely become dysregulated to promote chronic inflammation. Furthermore, macrophages are the predominant immunological cells in heart, adipose tissue, and lung, and these were primarily of the long-lived macrophage subset. Information about macrophages garnered from the SIV rhesus macaque model provides a basis to further develop intervention strategies that target macrophages for reducing chronic inflammatory co-morbidities and remove a contributing viral reservoir for achieving cure.
... These cells are thought to be repopulated in normal physiology at a rate that is augmented with HIV and SIV infection, inflammatory responses, and aging. Monocyte and monocyte/macrophages as well as resident tissue macrophages are critical in immune responses to retroviruses and by definition can be infected by them, but also play important roles in amplifying and toning immune responses, mediating lesion resolution, wound healing and repair [7,8]. With continued long-term immune stimulation by HIV and SIV in response to cell and tissue injury and death signals, and most importantly aging, these cells contribute to chronic immune activation termed "inflamm-aging", seen with aging and HIV [9][10][11][12]. ...
Before the antiretroviral therapy (ART) era, people living with HIV (PLWH) experienced complications due to AIDS more so than aging. With ART and the extended lifespan of PLWH, HIV comorbidities also include aging—most likely due to accelerated aging—as well as a cardiovascular, neurocognitive disorders, lung and kidney disease, and malignancies. The broad evidence suggests that HIV with ART is associated with accentuated aging, and that the age-related comorbidities occur earlier, due in part to chronic immune activation, co-infections, and possibly the effects of ART alone. Normally the immune system undergoes alterations of lymphocyte and monocyte populations with aging, that include diminished naïve T- and B-lymphocyte numbers, a reliance on memory lymphocytes, and a skewed production of myeloid cells leading to age-related inflammation, termed “inflamm-aging”. Specifically, absolute numbers and relative proportions of monocytes and monocyte subpopulations are skewed with age along with myeloid mitochondrial dysfunction, resulting in increased accumulation of reactive oxygen species (ROS). Additionally, an increase in biomarkers of myeloid activation (IL-6, sCD14, and sCD163) occurs with chronic HIV infection and with age, and may contribute to immunosenescence. Chronic HIV infection accelerates aging; meanwhile, ART treatment may slow age-related acceleration, but is not sufficient to stop aging or age-related comorbidities. Overall, a better understanding of the mechanisms behind accentuated aging with HIV and the effects of myeloid activation and turnover is needed for future therapies.
... The HIV-exposed but uninfected bystander cells play a critical role in HIV pathogenesis and disease progression by causing selective depletion of CD4 + T cells, leading to immunodeficiency 43 . Although HIV infection of T cells and macrophages differ with respect to cell death in vivo and in vitro 1,14,17,18 , uninfected bystander macrophages may also play a crucial role in HIV pathogenesis. Therefore, we determined if SMs induce apoptosis of HIV-exposed uninfected bystander macrophages. ...
Macrophages serve as viral reservoirs due to their resistance to apoptosis and HIV-cytopathic effects. We have previously shown that inhibitor of apoptosis proteins (IAPs) confer resistance to HIV-Vpr-induced apoptosis in normal macrophages. Herein, we show that second mitochondrial activator of caspases (SMAC) mimetics (SM) induce apoptosis of monocyte-derived macrophages (MDMs) infected in vitro with a R5-tropic laboratory strain expressing heat stable antigen, chronically infected U1 cells, and ex-vivo derived MDMs from HIV-infected individuals. To understand the mechanism governing SM-induced cell death, we show that SM-induced cell death of primary HIV-infected macrophages was independent of the acquisition of M1 phenotype following HIV infection of macrophages. Instead, SM-induced cell death was found to be mediated by IAPs as downregulation of IAPs by siRNAs induced cell death of HIV-infected macrophages. Moreover, HIV infection caused receptor interacting protein kinase-1 (RIPK1) degradation which in concert with IAP1/2 downregulation following SM treatment may result in apoptosis of macrophages. Altogether, our results show that SM selectively induce apoptosis in primary human macrophages infected in vitro with HIV possibly through RIPK1. Moreover, modulation of the IAP pathways may be a potential strategy for selective killing of HIV-infected macrophages in vivo.
... The latent HIV reservoir is defined as cells carrying integrated, replication-competent provirus that do not express viral transcripts or proteins (1). CD4 + T cells are recognized as the predominant cellular refuge for the latent HIV reservoir; specifically resting memory cells have been shown to be enriched in HIV provirus compared to other CD4 + T cell subsets, however cells from the myeloid lineage can also be infected by HIV and contribute to persistence of latency (2)(3)(4). Studies of antiretroviral therapy (ART) initiation during acute infection in humans and non-human primates (NHP) have shown that the latent reservoir is established very early following HIV infection (5,6). This is likely due to the ability of latently infected cells to distribute throughout the tissues with a higher viral burden detected in the gut, lymph nodes, and CNS relative to peripheral blood (7)(8)(9). ...
HIV eradication is hindered by the existence of latent HIV reservoirs in CD4⁺ T cells. Therapeutic strategies targeting latent cells are required to achieve a functional cure, however the study of latently infected cells from HIV infected persons is extremely challenging due to the lack of biomarkers that uniquely characterize them. In this study, the dual reporter virus HIVGKO was used to investigate latency establishment and maintenance in lymphoid-derived CD4⁺ T cells. Single cell technologies to evaluate protein expression, host gene expression, and HIV transcript expression were integrated to identify and analyze latently infected cells. FDA-approved, JAK1/2 inhibitors were tested in this system as a potential therapeutic strategy to target the latent reservoir. Latent and productively infected tonsillar CD4⁺ T cells displayed similar activation profiles as measured by expression of CD69, CD25, and HLADR, however latent cells showed higher CXCR5 expression 3 days post-infection. Single cell analysis revealed a small set of genes, including HIST1-related genes and the inflammatory cytokine, IL32, that were upregulated in latent compared to uninfected and productively infected cells suggesting a role for these molecular pathways in persistent HIV infection. In vitro treatment of HIV-infected CD4⁺ T cells with physiological concentrations of JAK1/2 inhibitors, ruxolitinib and baricitinib, used in clinical settings to target inflammation, reduced latent and productive infection events when added 24 hr after infection and blocked HIV reactivation from latent cells. Our methods using an established model of HIV latency and lymphoid-derived cells shed light on the biology of latency in a crucial anatomical site for HIV persistence and provides key insights about repurposing baricitinib or ruxolitinib to target the HIV reservoir.
... BDZs have well-described pharmacokinetics and penetrate the blood-brain barrier (32,33), making them an attractive therapy to address issues in the CNS. Persistent HIV-1 infection of CNS reservoirs drives a spectrum of neuropathologic, behavioral, and cognitive effects (34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Even with effective ART therapy, these neuropathologies are apparent in HIV-1 infected individuals (44,45). ...
... Neuroinflammation is a major factor of several neurodegenerative disorders including neuroHIV-1 (91-95). Neuroinflammation can contribute to neuronal and immune damage through the chronic activation of microglia and perivascular macrophages of the CNS (15,(35)(36)(37)(38). Myeloid cells are long-lived and resistant to cell death caused by infection (35,37), making them a platform to drive neuroinflammatory events in subjects on suppressive ART therapy. ...
The HIV-1 pandemic is a significant challenge to the field of medicine. Despite advancements in antiretroviral (ART) development, 38 million people worldwide still live with this disease without a cure. A significant barrier to the eradication of HIV-1 lies in the persistently latent pool that establishes early in the infection. The “shock and kill” strategy relies on the discovery of a latency-reversing agent (LRA) that can robustly reactivate the latent pool and not limit immune clearance. We have found that a benzodiazepine (BDZ), that is commonly prescribed for panic and anxiety disorder, to be an ideal candidate for latency reversal. The BDZ Alprazolam functions as an inhibitor of the transcription factor RUNX1, which negatively regulates HIV-1 transcription. In addition to the displacement of RUNX1 from the HIV-1 5′LTR, Alprazolam potentiates the activation of STAT5 and its recruitment to the viral promoter. The activation of STAT5 in cytotoxic T cells may enable immune activation which is independent of the IL-2 receptor. These findings have significance for the potential use of Alprazolam in a curative strategy and to addressing the neuroinflammation associated with neuroHIV-1.
... Macrophages play an important role in the immunopathogenesis of HIV infection and the development of acquired immunodeficiency syndrome (AIDS). Macrophages, along with CD4 + T cells, are the major targets of HIV [2,3]. Because macrophages express both the primary receptor CD4 and co-receptor CCR5, they are highly susceptible to productive infection by CCR5-tropic HIV strains [4]. ...
... When compared to CD4 + T cells, HIV-infected macrophages are more resistant to apoptosis and less sensitive to ART. These pathological properties of macrophages make them an ideal reservoir for HIV persistence and latency as well as a therapeutic target [2,6]. In addition, because of their ability to infiltrate virtually all organs, HIV-infected macrophages contribute to the spread of the virus [3]. ...
The Toll-like receptor (TLR) 7 is a viral sensor for detecting single-stranded ribonucleic acid (ssRNA), the activation of which can induce intracellular innate immunity against viral infections. Imiquimod, a synthetic ligand for TLR7, has been successfully used for the topical treatment of genital/perianal warts in immunocompetent individuals. We studied the effect of imiquimod on the human immunodeficiency virus (HIV) infection of primary human macrophages and demonstrated that the treatment of cells with imiquimod effectively inhibited infection with multiple strains (Bal, YU2, and Jago) of HIV. This anti-HIV activity of imiquimod was the most potent when macrophages were treated prior to infection. Infection of macrophages with pseudotyped HIV NL4-3-∆Env-eGFP-Bal showed that imiquimod could block the viral entry. Further mechanistic studies revealed that while imiquimod had little effect on the interferons (IFNs) expression, its treatment of macrophages resulted in the increased production of the CC chemokines (human macrophage inflammatory protein-1 alpha (MIP-1α), MIP-1β, and upon activation regulated normal T cells expressed and secreted (RANTES)), the natural ligands of HIV entry co-receptor CCR5, and decreased the expression of CD4 and CCR5. The addition of the antibodies against the CC chemokines to macrophage cultures could block imiquimod-mediated HIV inhibition. These findings provide experimental evidence to support the notion that TLR7 participates in the intracellular immunity against HIV in macrophages, suggesting the further clinical evaluation of imiquimod for its additional benefit of treating genital/perianal warts in people infected with HIV.
