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Modulation of macrophage activity by cytokines. Classical activation of macrophages by IFN- γ which display pro-inflammatory characteristics while the alternative activation is mediated by IL-4 and IL-13 and express anti-inflammatory or tissue repairing properties. Macrophages can be deactivated by IL-10.
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Human immunodeficiency virus type 1 (HIV-1) establishes latency in resting memory CD4+ T cells and cells of myeloid lineage. In contrast to the T cells, cells of myeloid lineage are resistant to the HIV-1 induced cytopathic effect. Cells of myeloid lineage including macrophages are present in anatomical sanctuaries making them a difficult drug targ...
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Context 1
... play a crucial role in the initial infection, and contribute to HIV-1 pathogenesis throughout the course of viral infection. Since macrophages are an important part of innate immunity and participate indirectly to the adaptive immunity to clear the infection, this makes them a central target of HIV-1 [37,42 – 50]. HIV-1 targets the monocyte/macrophage lineage at varying stages of differentiation [48,49]. For instance data suggests the involvement of a particular monocyte subtype in HIV-1 infection [51]. Phenotypical comparative studies demonstrate that CD14 ++ CD16 + monocytes are more permissive to productive HIV-1 infection and harbor HIV-1 in infected individuals on cART as compare to the majority of blood monocytes (CD14 ++ CD16 − ). In healthy individuals, the CD14 ++ CD16 + monocytes represent 10% of circulating monocytes [52]. The characteristics have been studied in rhesus macaques. In acute infection, there was an increase in CD14 ++ CD16 + and CD14 + CD16 ++ monocytes, while CD14 ++ CD16 − monocytes decreased two weeks after infection [53]. Similarly, there was increase in CD14 ++ CD16 + and CD14 + CD16 ++ monocytes subsets in rhesus macaques with chronic infection and high viral load [53,54]. Moreover, in HIV-1 infected patients, the preferential expansion of CD14 ++ CD16 + monocyte subset is associated with increased intracellular level of CCL2 [55]. CCL-2 is an important pro-inflammatory chemokine produced during HIV-1 infection and is one of the key factors responsible for the chronic inflammation and tissue damage in HIV-infected patients [56]. For instance, Cinque and colleagues reported a positive correlation between the levels of CCL2 in cerebrospinal fluid of patients with the severity of HIV-1 encephalitis [57]. In another instance, role of CCL-2 has been shown in enhancing the replication of HIV-1 in PBMCs isolated from patients [58]. These monocyte subsets (CD14 ++ CD16 + and CD14 + CD16 ++ ) have been also reported in HCV infection demonstrating that CD16 + monocytes may play important role in viral diseases [59,60]. Monocyte derived macrophages exhibits two distinct types of polarization states depending upon the presence or absence of specific microenvironment stimuli including cytokines. Interestingly, these cytokines also govern HIV-1 pathogenesis. These activation states (classically activated (M1) and alternatively activated macrophages (M2)) play an important role in mediating an effective immune response against infectious agents including HIV-1 [61 – 65] (Figure 1). The M1 macrophages are activated by a high amount of Th1 cytokines (IFN- γ, IL-2, IL-12), pro-inflammatory cytokines (TNF- α, IL- 1β, IL-6, IL-18) and chemokines (CCL3, CCL4, CCL5) that enhance viral replication and block viral entry to prevent superinfection in infected macrophages [64] (Figure 1). M1 macrophages express classical pro-inflammatory cytokines such as TNF- α while M2 macrophages produce anti-inflammatory cytokines such as IL-4, TGF- β and IL-10 by a high amount [62]. During early stages of infection, the M1 macrophages are predominant which cause the tissue injury specifically in lymph nodes that is correlated with T cell apoptosis [66]. However, at later stages of viral infection, there is a shift of M1 to M2 due to the presence of IL-4 and IL-13. The M2 macrophages favor tissue repair and help to clear the opportunistic infections during HIV-1 infection. The progression of HIV-1 infection is accompanied by depletion of CD4+ T cells, resulting in frequent opportunistic infections and the imbalance of Th1 and Th2 responses leads towards the progression of AIDS ...
Context 2
... play a crucial role in the initial infection, and contribute to HIV-1 pathogenesis throughout the course of viral infection. Since macrophages are an important part of innate immunity and participate indirectly to the adaptive immunity to clear the infection, this makes them a central target of HIV-1 [37,42 – 50]. HIV-1 targets the monocyte/macrophage lineage at varying stages of differentiation [48,49]. For instance data suggests the involvement of a particular monocyte subtype in HIV-1 infection [51]. Phenotypical comparative studies demonstrate that CD14 ++ CD16 + monocytes are more permissive to productive HIV-1 infection and harbor HIV-1 in infected individuals on cART as compare to the majority of blood monocytes (CD14 ++ CD16 − ). In healthy individuals, the CD14 ++ CD16 + monocytes represent 10% of circulating monocytes [52]. The characteristics have been studied in rhesus macaques. In acute infection, there was an increase in CD14 ++ CD16 + and CD14 + CD16 ++ monocytes, while CD14 ++ CD16 − monocytes decreased two weeks after infection [53]. Similarly, there was increase in CD14 ++ CD16 + and CD14 + CD16 ++ monocytes subsets in rhesus macaques with chronic infection and high viral load [53,54]. Moreover, in HIV-1 infected patients, the preferential expansion of CD14 ++ CD16 + monocyte subset is associated with increased intracellular level of CCL2 [55]. CCL-2 is an important pro-inflammatory chemokine produced during HIV-1 infection and is one of the key factors responsible for the chronic inflammation and tissue damage in HIV-infected patients [56]. For instance, Cinque and colleagues reported a positive correlation between the levels of CCL2 in cerebrospinal fluid of patients with the severity of HIV-1 encephalitis [57]. In another instance, role of CCL-2 has been shown in enhancing the replication of HIV-1 in PBMCs isolated from patients [58]. These monocyte subsets (CD14 ++ CD16 + and CD14 + CD16 ++ ) have been also reported in HCV infection demonstrating that CD16 + monocytes may play important role in viral diseases [59,60]. Monocyte derived macrophages exhibits two distinct types of polarization states depending upon the presence or absence of specific microenvironment stimuli including cytokines. Interestingly, these cytokines also govern HIV-1 pathogenesis. These activation states (classically activated (M1) and alternatively activated macrophages (M2)) play an important role in mediating an effective immune response against infectious agents including HIV-1 [61 – 65] (Figure 1). The M1 macrophages are activated by a high amount of Th1 cytokines (IFN- γ, IL-2, IL-12), pro-inflammatory cytokines (TNF- α, IL- 1β, IL-6, IL-18) and chemokines (CCL3, CCL4, CCL5) that enhance viral replication and block viral entry to prevent superinfection in infected macrophages [64] (Figure 1). M1 macrophages express classical pro-inflammatory cytokines such as TNF- α while M2 macrophages produce anti-inflammatory cytokines such as IL-4, TGF- β and IL-10 by a high amount [62]. During early stages of infection, the M1 macrophages are predominant which cause the tissue injury specifically in lymph nodes that is correlated with T cell apoptosis [66]. However, at later stages of viral infection, there is a shift of M1 to M2 due to the presence of IL-4 and IL-13. The M2 macrophages favor tissue repair and help to clear the opportunistic infections during HIV-1 infection. The progression of HIV-1 infection is accompanied by depletion of CD4+ T cells, resulting in frequent opportunistic infections and the imbalance of Th1 and Th2 responses leads towards the progression of AIDS ...
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Despite antiretroviral therapy (ART), HIV persistence in the central nervous system (CNS) continues to cause a range of cognitive impairments in people living with HIV (PLWH). Upon disease progression, transmigrating CCR5-using T-cell tropic viruses are hypothesized to evolve into macrophage-tropic viruses in the CNS that can efficiently infect low...
Citations
... killed by active virus replication (1). This feature enables infected myeloid cells to serve as long-term reservoirs in vivo, particularly in the CNS, where their sustained long-term low-level viral expression may also contribute to neurocognitive complica tions that develop despite antiretroviral therapy (2)(3)(4)(5). ...
HIV establishes long-term latent infection in memory CD4⁺ T cells and also establishes sustained long-term productive infection in macrophages, especially in the central nervous system (CNS). To better understand how HIV sustains infection in macrophages, we performed RNAseq analysis after infection of human monocyte-derived macrophages (MDMs) with the brain-derived HIV-1 strain YU2 and compared this with acute infection of CD4⁺ T cells. HIV infection in MDM and CD4⁺ T cells altered many gene transcripts, but with few overlaps between these different cell types. We found interferon pathways upregulated in both MDM and CD4⁺ T cells, but with different gene signatures. The interferon-stimulated gene RSAD2/Viperin was among the most upregulated genes following HIV infection in MDMs, but not in CD4⁺ T cells. RSAD2/Viperin was induced early after infection with various HIV strains, was sustained over time, and remained elevated in established MDM infection even if new rounds of infection were blocked by antiretroviral treatment. Immunofluorescence microscopy revealed that RSAD2/Viperin was induced in HIV-infected cells, as well as in some uninfected neighboring cells. Knockdown of RSAD2/Viperin following the establishment of infection in MDMs reduced the production of HIV transcripts and viral p24 antigen. This correlated with the reduction in the number of multinucleated giant cells, and changes in the HIV DNA and chromatin structure, including an increased DNA copy number and loss of nucleosomes and histone modifications at the long terminal repeat (LTR). RNAseq transcriptomic analysis of RSAD2/Viperin knockdown during HIV infection of MDMs revealed the activation of interferon alpha/beta and gamma pathways and the inactivation of Rho GTPase pathways. Taken together, these results suggest that RSAD2/Viperin supports the sustained infection in macrophages, potentially through mechanisms involving the alteration of the LTR chromatin structure and the interferon response.
IMPORTANCE
HIV infection of macrophages is a barrier to HIV cure and a source of neurocognitive pathology. We found that HIV induces RSAD2/Viperin during sustained infection of macrophages. While RSAD2/Viperin is an interferon-stimulated gene with known antiviral activity, we find RSAD2/Viperin promotes HIV infection in macrophages through multiple mechanisms, including interferon signaling. Therefore, RSAD2/Viperin may be a therapeutic target for the treatment of HIV-infected macrophages.
... Macrophages infected with HIV-1 demonstrate increased resistance to apoptosis and decreased sensitivity to combination antiretroviral therapy. These features make macrophages the optimal HIV-1 reservoirs and a key focus for therapeutic intervention [15,16,[20][21][22]]. An early study [22] reported that TLR5 activation by flagellin could activate NF-κB and latent HIV-1 in CD4 + T cells in HIV-1-infected individuals. ...
Both bacteria product flagellin and macrophages are implicated in HIV-1 infection/disease progression. However, the impact of their interaction on HIV-1 infection and the associated mechanisms remain to be determined. We thus examined the effect of the flagellins on HIV-1 infection of primary human macrophages. We observed that the pretreatment of macrophages with the flagellins from the different bacteria significantly inhibited HIV-1 infection. The mechanistic investigation showed that the flagellin treatment of macrophages downregulated the major HIV-1 entry receptors (CD4 and CCR5) and upregulated the CC chemokines (MIP-1α, MIP-1β and RANTES), the ligands of CCR5. These effects of the flagellin could be compromised by a toll-like receptor 5 (TLR5) antagonist. Given the important role of flagellin as a vaccine adjuvant in TLR5 activation-mediated immune regulation and in HIV-1 infection of macrophages, future investigations are necessary to determine the in vivo impact of flagellin–TLR5 interaction on macrophage-mediated innate immunity against HIV-1 infection and the effectiveness of flagellin adjuvant-based vaccines studies.
... Macrophages infected with HIV demonstrate increased resistance to apoptosis and decreased sensitivity to combination antiretroviral therapy. These features make macrophages the optimal HIV reservoirs and a key focus for therapeutic intervention [15,16,[20][21][22]]. An early study [22] reported that TLR5 activation by flagellin could activate NF-ĸB and latent HIV in CD4+ T cells in HIV-infected individuals. ...
Both bacteria product flagellin and macrophages are implicated in HIV infection/disease progression. However, the impact of their interaction on HIV infection and the associated mechanisms remain to be determined. We thus examined the effect of the flagellins on HIV infection of primary human macrophages. We observed that the pretreatment of macrophages with the flagellins from the different bacteria significantly inhibited HIV infection. The mechanistic investigation showed that the flagellin treatment of macrophages downregulated the major HIV entry receptors (CD4 and CCR5) and upregulated the CC chemokines (MIP-1α, MIP-1β, and RANTES), the ligands of CCR5. These effects of the flagellin could be compromised by a toll like receptor 5 (TLR5) antagonist. Given the important role of flagellin as a vaccine adjuvant in TLR5 activation-mediated immune regulation and in HIV infection of macrophages, future investigations are necessary to determine the in vivo impact of flagellin-TLR5 interaction on macrophage-mediated innate immunity against HIV infection and the effectiveness of flagellin adjuvant-based vaccines studies.
... Upon viral infection, macrophages respond with an enhanced expression of inflammatory cytokines (-pro and -anti) which leads to an activated antiviral immune response [4]. Several studies report that viruses persist in macrophages for extended periods that may have a direct bearing on disease progression [5][6][7][8][9]. ...
Macrophages are efficient reservoirs for viruses that enable the viruses to survive over a longer period of infection. Alphaviruses such as chikungunya virus (CHIKV) are known to persist in macrophages even after the acute febrile phase. The viral particles replicate in macrophages at a very low level over extended period of time and are localized in tissues that are often less accessible by treatment. Comprehensive experimental studies are thus needed to characterize the CHIKV-induced modulation of host genes in these myeloid lineage cells and in one such pursuit, we obtained global transcriptomes of a human macrophage cell line infected with CHIKV, over its early and late timepoints of infection. We analyzed the pathways, especially immune related, perturbed over these timepoints and observed several host factors to be differentially expressed in infected macrophages in a time-dependent manner. We postulate that these pathways may play crucial roles in the persistence of CHIKV in macrophages.
... Although the role of resting memory CD4 + T cells as a reservoir of HIV infection has been clearly established, there is evidence that macrophages also represent a durable HIV reservoir. Tissue-resident macrophages, including microglia in the central nervous system (CNS), have a lifespan of months to years and are resistant to the cytopathic effects of HIV 24,25 . Studies in both SIV-infected macaques and HIV-infected humanized mice demonstrate that tissue macrophages are productively infected and represent a source of rebound viremia upon cessation of ART 15,26,27 . ...
Although the world is currently focused on the COVID-19 pandemic, HIV/AIDS remains a significant threat to public health. To date, the HIV/AIDS pandemic has claimed the lives of over 36 million people, while nearly 38 million people are currently living with the virus. Despite the undeniable success of antiretroviral therapy (ART) in controlling HIV, the medications are not curative. Soon after initial infection, HIV integrates into the genome of infected cells as a provirus, primarily, within CD4+ T lymphocytes and tissue macrophages. When not actively transcribed, the provirus is referred to as a latent reservoir because it is hidden to the immune system and ART. Following ART discontinuation, HIV may emerge from the replication-competent proviruses and resumes the infection of healthy cells. Thus, these latent reservoirs are a major obstacle to an HIV cure, and their removal remains a priority. A vital aspect in the development of curative therapies is the demonstration of efficacy in an animal model, such as the humanized mouse model. Therefore, optimization, standardization, and validation of the humanized mouse model are a priority. The purpose of this review article is to provide an update on existing humanized mouse models, highlighting the advantages and disadvantages of each as they pertain to HIV cure studies and to review the approaches to curative therapies that are under investigation.
... HIV-1 cell-to-cell transfer between CD4+ T cells, mainly through the formation of the so-called virological synapse [40][41][42] , or from infected macrophages or dendritic cells to CD4+ T cell targets, have been extensively described in vitro 23,[43][44][45][46][47][48][49] , In addition, recent reports demonstrate that myeloid cells can be also productively infected through virus cell-to-cell transfer for more efficient spreading in these poorly susceptible cell types. Since myeloid cells are now emerging as important target cells involved in all steps of HIV-1 pathogenesis and in viral persistence in tissues of infected individuals 10,50,51 , even under conditions of anti-retroviral treatment, the goal of this review is to discuss the different mechanisms reported in the literature regarding HIV-1 cell-to-cell spread leading to productive infection of myeloid cells. The first part of the review will be related to the mechanisms of homotypic virus cell-to-cell transfer between macrophages, while the second part will focus on the two different mechanisms reported for heterotypic virus cell-to-cell dissemination from virus-donor infected CD4+ T cells to myeloid cell targets, including macrophages, DCs and OCs. ...
In addition to CD4+ T lymphocytes, cells of the myeloid lineage such as macrophages, dendritic cells (DCs), and osteoclasts (OCs) are emerging as important target cells for HIV‐1, as they likely participate in all steps of pathogenesis, including sexual transmission and early virus dissemination in both lymphoid and nonlymphoid tissues where they can constitute persistent virus reservoirs. At least in vitro, these myeloid cells are poorly infected by cell‐free viral particles. In contrast, intercellular virus transmission through direct cell‐to‐cell contacts may be a predominant mode of virus propagation in vivo leading to productive infection of these myeloid target cells. HIV‐1 cell‐to‐cell transfer between CD4+ T cells mainly through the formation of the virologic synapse, or from infected macrophages or dendritic cells to CD4+ T cell targets, have been extensively described in vitro. Recent reports demonstrate that myeloid cells can be also productively infected through virus homotypic or heterotypic cell‐to‐cell transfer between macrophages or from virus‐donor‐infected CD4+ T cells, respectively. These modes of infection of myeloid target cells lead to very efficient spreading in these poorly susceptible cell types. Thus, the goal of this review is to give an overview of the different mechanisms reported in the literature for cell‐to‐cell transfer and spreading of HIV‐1 in myeloid cells. Review of the mechanisms involved in HIV‐1 cell‐to‐cell transfer to myeloid cells.
... Another distinguishing feature of macrophage infection is that they are long-lived cells yet resistant to HIV-induced killing, and productively infected macrophages persist for prolonged periods, unlike activated CD4 1 T cells that are killed by active virus replication (8,15,16). This feature enables infected myeloid cells to serve as long-term reservoirs in vivo, particularly in the CNS (17)(18)(19)(20). Finally, while the resting CD4 1 T cell long-term reservoir is typically thought of as latent, low-level virus expression generally persists throughout the life span of infected macrophages (17,(21)(22)(23). ...
... This feature enables infected myeloid cells to serve as long-term reservoirs in vivo, particularly in the CNS (17)(18)(19)(20). Finally, while the resting CD4 1 T cell long-term reservoir is typically thought of as latent, low-level virus expression generally persists throughout the life span of infected macrophages (17,(21)(22)(23). Indeed, persistent low-level virus expression from long-lived infected brain macrophages is thought to be a driver of neurological complications that occur in infected people despite ART (24,25). ...
Human immunodeficiency virus (HIV)-infected macrophages are long-lived cells that sustain persistent virus expression, which is both a barrier to viral eradication and contributor to neurological complications in patients despite antiretroviral therapy (ART). To better understand the regulation of HIV-1 in macrophages, we compared HIV-infected primary human monocyte-derived macrophages (MDM) to acutely infected primary CD4 T cells and Jurkat cells latently infected with HIV (JLAT 8.4). HIV genomes in MDM were actively transcribed despite enrichment with heterochromatin-associated H3K9me3 across the complete HIV genome in combination with elevated activation marks of H3K9ac and H3K27ac at the long terminal repeat (LTR). Macrophage patterns contrasted with JLAT cells, which showed conventional bivalent H3K4me3/H3K27me3, and acutely infected CD4 T cells, which showed an intermediate epigenotype. 5′-Methylcytosine (5mC) was enriched across the HIV genome in latently infected JLAT cells, while 5′-hydroxymethylcytosine (5hmC) was enriched in CD4 cells and MDMs. HIV infection induced multinucleation of MDMs along with DNA damage-associated p53 phosphorylation, as well as loss of TET2 and the nuclear redistribution of 5-hydoxymethylation. Taken together, our findings suggest that HIV induces a unique macrophage nuclear and transcriptional profile, and viral genomes are maintained in a noncanonical bivalent epigenetic state.
IMPORTANCE Macrophages serve as a reservoir for long-term persistence and chronic production of HIV. We found an atypical epigenetic control of HIV in macrophages marked by heterochromatic H3K9me3 despite active viral transcription. HIV infection induced changes in macrophage nuclear morphology and epigenetic regulatory factors. These findings may identify new mechanisms to control chronic HIV expression in infected macrophages.
... 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]. ...
... Infected macrophages are detected throughout the body [3,4,[41][42][43][44][45][46][47][48][49][50]. Furthermore, resident macrophages infected with virus are resistant to apoptosis [17,42,[51][52][53] and cytotoxic CD8 T cell lysis [54] thereby supporting their likely contribution to the virus reservoir. ...
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.
... Few HIV-1-infected macrophages undergo apoptosis, consistent with the viruses' need for long-term residency and reproduction in splenic macrophages. These macrophages have a central role in HIV infection and deregulatory changes in the spleen [108,130,131]. Thus, both viral titers and viral replication are low during viral latency, but are sufficient to sustain chronic infection. ...
The immune and sympathetic nervous systems are major targets of human, murine and simian immunodeficiency viruses (HIV-1, MAIDS, and SIV, respectively). The spleen is a major reservoir for these retroviruses, providing a sanctuary for persistent infection of myeloid cells in the white and red pulps. This is despite the fact that circulating HIV-1 levels remain undetectable in infected patients receiving combined antiretroviral therapy. These viruses sequester in immune organs, preventing effective cures. The spleen remains understudied in its role in HIV-1 pathogenesis, despite it hosting a quarter of the body’s lymphocytes and diverse macrophage populations targeted by HIV-1. HIV-1 infection reduces the white pulp, and induces perivascular hyalinization, vascular dysfunction, tissue infarction, and chronic inflammation characterized by activated epithelial-like macrophages. LP-BM5, the retrovirus that induces MAIDS, is a well-established model of AIDS. Immune pathology in MAIDs is similar to SIV and HIV-1 infection. As in SIV and HIV, MAIDS markedly changes splenic architecture, and causes sympathetic dysfunction, contributing to inflammation and immune dysfunction. In MAIDs, SIV, and HIV, the viruses commandeer splenic macrophages for their replication, and shift macrophages to an M2 phenotype. Additionally, in plasmacytoid dendritic cells, HIV-1 blocks sympathetic augmentation of interferon-β (IFN-β) transcription, which promotes viral replication. Here, we review viral–sympathetic interactions in innate immunity and pathophysiology in the spleen in HIV-1 and relevant models. The situation remains that research in this area is still sparse and original hypotheses proposed largely remain unanswered.
... This inhibition also induces a block of p28 and ERK1/2 activation and appears to be mediated by CCR5. This could allow the targeting of viralinduced proinflammatory cytokine production in macrophages, to slow HIV pathogenesis (Abbas et al., 2015;Pasquereau et al., 2018). ...
The protein kinase B or Akt is a central regulator of survival, metabolism, growth and proliferation of the cells and is known to be targeted by various viral pathogens, including HIV-1. The central role of Akt makes it a critical player in HIV-1 pathogenesis, notably by affecting viral entry, latency and reactivation, cell survival, viral spread and immune response to the infection. Several HIV proteins activate the PI3K/Akt pathway, to fuel the progression of the infection. Targeting Akt could help control HIV-1 entry, viral latency/replication, cell survival of infected cells, HIV spread from cell-to-cell, and the immune microenvironment which could ultimately allow to curtail the size of the HIV reservoir. Beside the “shock and kill” and “block and lock” strategies, the use of Akt inhibitors in combination with latency inducing agents, could favor the clearance of infected cells and be part of new therapeutic strategies with the goal to “block and clear” HIV.
