The Potential Contribution of Caveolin 1 to HIV Latent Infection

Combinatorial antiretroviral therapy (cART) suppresses HIV replication to undetectable levels and has been effective in prolonging the lives of HIV infected individuals. However, cART is not capable of eradicating HIV from infected individuals mainly due to HIV’s persistence in small reservoirs of latently infected resting cells. Latent infection occurs when the HIV-1 provirus becomes transcriptionally inactive and several mechanisms that contribute to the silencing of HIV transcription have been described. Despite these advances, latent infection remains a major hurdle to cure HIV infected individuals. Therefore, there is a need for more understanding of novel mechanisms that are associated with latent infection to purge HIV from infected individuals thoroughly. Caveolin 1(Cav-1) is a multifaceted functional protein expressed in many cell types. The expression of Cav-1 in lymphocytes has been controversial. Recent evidence, however, convincingly established the expression of Cav-1 in lymphocytes. In lieu of this finding, the current review examines the potential role of Cav-1 in HIV latent infection and provides a perspective that helps uncover new insights to understand HIV latent infection.

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Latently KSHV-Infected Cells Promote Further Establishment of Latency upon Superinfection with KSHV

International Journal of Molecular Sciences ◽

10.3390/ijms222111994 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11994

Author(s):

Chen Gam ze Letova ◽

Inna Kalt ◽

Meir Shamay ◽

Ronit Sarid

Keyword(s):

Latent Infection ◽

Fluorescent Proteins ◽

Cell Types ◽

Lytic Cycle ◽

Viral Reservoir ◽

Virus Spread ◽

Viral Genomes ◽

Latently Infected ◽

Infected Cells

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a cancer-related virus which engages in two forms of infection: latent and lytic. Latent infection allows the virus to establish long-term persistent infection, whereas the lytic cycle is needed for the maintenance of the viral reservoir and for virus spread. By using recombinant KSHV viruses encoding mNeonGreen and mCherry fluorescent proteins, we show that various cell types that are latently-infected with KSHV can be superinfected, and that the new incoming viruses establish latent infection. Moreover, we show that latency establishment is enhanced in superinfected cells compared to primary infected ones. Further analysis revealed that cells that ectopically express the major latency protein of KSHV, LANA-1, prior to and during infection exhibit enhanced establishment of latency, but not cells expressing LANA-1 fragments. This observation supports the notion that the expression level of LANA-1 following infection determines the efficiency of latency establishment and avoids loss of viral genomes. These findings imply that a host can be infected with more than a single viral genome and that superinfection may support the maintenance of long-term latency.

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Exploring HIV latency using transcription profiling

Microbiology Australia ◽

10.1071/ma17050 ◽

2017 ◽

Vol 38 (3) ◽

pp. 137

Author(s):

Sushama Telwatte ◽

Steven A Yukl

Keyword(s):

Transcriptional Profiling ◽

Cell Types ◽

Hiv Latency ◽

Dna Viruses ◽

Major Barrier ◽

Hiv Transcription ◽

Latently Infected ◽

Infected Cells ◽

Mechanisms Of Persistence

The major barrier to a cure for HIV is the existence of reservoirs consisting predominantly of latently infected CD4+ T cells, which do not produce virus constitutively but can be induced to produce infectious virus on activation. HIV latency research has largely focused on peripheral blood, yet most HIV-infected cells reside in tissues, especially the gut, where differences in drug penetration, cell types, and immune responses may impact mechanisms of persistence. Exploring the differences between the gut and the blood in transcriptional blocks may reveal fundamental insights into mechanisms that contribute to HIV latency. Our novel transcriptional profiling assays enable us to determine where blocks to HIV transcription occur in various tissues and the magnitude of their contribution. These assays could also be adapted to investigate latency established by other retroviridae or even DNA viruses such as herpesviridae with a view to pinpointing mechanisms underlying latency in vivo and ultimately contribute to designing a cure.

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Interaction between Endogenous Bacterial Flora and Latent HIV Infection

Clinical and Vaccine Immunology ◽

10.1128/cvi.00766-12 ◽

2013 ◽

Vol 20 (6) ◽

pp. 773-779 ◽

Cited By ~ 3

Author(s):

Ann Florence B. Victoriano ◽

Kenichi Imai ◽

Takashi Okamoto

Keyword(s):

Hiv Infection ◽

Opportunistic Infections ◽

Bacterial Flora ◽

Anaerobic Bacteria ◽

Hiv Replication ◽

Latently Infected ◽

Potential Link ◽

Infected Cells ◽

Latent Hiv

ABSTRACTHuman commensal bacteria do not normally cause any diseases. However, in certain pathological conditions, they exhibit a number of curious behaviors. In HIV infection, these bacteria exhibit bidirectional relationships: whereas they cause opportunistic infections based on immunological deterioration, they also augment HIV replication, in particular, viral replication from latently infected cells, which is attributable to the effect of butyric acid produced by certain anaerobic bacteria by modifying the state of chromatin. Here, we review recent evidence supporting the contributory role of such endogenous microbes in disrupting HIV latency and its potential link to the clinical progression of AIDS.

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Caveolin-1 and caveolin-3 form heterooligomeric complexes in atrial cardiac myocytes that are required for doxorubicin-induced apoptosis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01039.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. H392-H401 ◽

Cited By ~ 36

Author(s):

Daniela Volonte ◽

Charles F. McTiernan ◽

Marek Drab ◽

Michael Kasper ◽

Ferruccio Galbiati

Keyword(s):

Cardiac Myocytes ◽

Functional Role ◽

Cell Types ◽

Structural Protein ◽

Caveolin 1 ◽

Protein Components ◽

Induced Apoptosis ◽

First Time ◽

Rat Cardiac Myocytes

Caveolae are 50- to 100-nm invaginations of the plasma membrane. Caveolins are the structural protein components of caveolar membranes. The caveolin gene family is composed of three members: caveolin-1, caveolin-2, and caveolin-3. Caveolin-1 and caveolin-2 are coexpressed in many cell types, including adipocytes, endothelial cells, epithelial cells, and fibroblasts. In contrast, caveolin-3 expression is essentially restricted to skeletal and smooth muscle cells as well as cardiac myocytes. While the interaction between caveolin-1 and caveolin-2 has been documented previously, the reciprocal interaction between endogenous caveolin-1 and caveolin-3 and their functional role in cell types expressing both isoforms have yet to be identified. Here we demonstrate for the first time that caveolin-1 and caveolin-3 are coexpressed in mouse and rat cardiac myocytes of the atria but not ventricles. We also found that caveolin-1 and caveolin-3 can interact and form heterooligomeric complexes in this cell type. Doxorubicin is an effective anticancer agent, but its use is limited by the possible development of cardiotoxicity. Using caveolin-1- and caveolin-3-null mice, we show that both caveolin-1 and caveolin-3 expression are required for doxorubicin-induced apoptosis in the atria through activation of caspase 3. Together, these results bring new insight into the functional role of caveolae and suggest that caveolin-1/caveolin-3 heterooligomeric complexes may play a key role in chemotherapy-induced cardiotoxicity in the atria.

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Human Cytomegalovirus Latency-Associated Protein pORF94 Is Dispensable for Productive and Latent Infection

Journal of Virology ◽

10.1128/jvi.74.19.9333-9337.2000 ◽

2000 ◽

Vol 74 (19) ◽

pp. 9333-9337 ◽

Cited By ~ 40

Author(s):

Kirsten Lofgren White ◽

Barry Slobedman ◽

Edward S. Mocarski

Keyword(s):

Human Cytomegalovirus ◽

Latent Infection ◽

Cultured Cells ◽

Wild Type Virus ◽

Wild Type ◽

Reading Frame ◽

Latently Infected ◽

Infected Cells ◽

Latent Phase

ABSTRACT Human cytomegalovirus latency in bone marrow-derived myeloid progenitors is characterized by the presence of latency-associated transcripts encoded in the ie1/ie2 region of the viral genome. To assess the role of ORF94 (UL126a), a conserved open reading frame on these transcripts, a recombinant virus (RC2710) unable to express this gene was constructed. This virus replicated at wild-type levels and expressed productive as well as latency-associatedie1/ie2 region transcripts. During latency in granulocyte-macrophage progenitors, RC2710 DNA was detected at levels indistinguishable from wild-type virus, latent-phase transcription was present, and RC2710 reactivated when latently infected cells were cocultured with permissive fibroblasts. These data suggest pORF94 is not required for either productive or latent infection as assayed in cultured cells despite being the only known nuclear latency-associated protein.

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Control of Cytokines in Latent Cytomegalovirus Infection

Pathogens ◽

10.3390/pathogens9100858 ◽

2020 ◽

Vol 9 (10) ◽

pp. 858

Author(s):

Pearley Chinta ◽

Erica C. Garcia ◽

Kiran Hina Tajuddin ◽

Naomi Akhidenor ◽

Allyson Davis ◽

...

Keyword(s):

Latent Infection ◽

Cell Types ◽

Cytokine Signaling ◽

Host Immune System ◽

Myeloid Progenitor ◽

Wide Range ◽

Latently Infected ◽

Myeloid Progenitor Cells ◽

Infected Cells

Human cytomegalovirus (HCMV) has evolved a number of mechanisms for long-term co-existence within its host. HCMV infects a wide range of cell types, including fibroblasts, epithelial cells, monocytes, macrophages, dendritic cells, and myeloid progenitor cells. Lytic infection, with the production of infectious progeny virions, occurs in differentiated cell types, while undifferentiated myeloid precursor cells are the primary site of latent infection. The outcome of HCMV infection depends partly on the cell type and differentiation state but is also influenced by the composition of the immune environment. In this review, we discuss the role of early interactions between HCMV and the host immune system, particularly cytokine and chemokine networks, that facilitate the establishment of lifelong latent infection. A better understanding of these cytokine signaling pathways could lead to novel therapeutic targets that might prevent latency or eradicate latently infected cells.

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Role of caveolin and caveolae in insulin signaling and diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00324.2003 ◽

2003 ◽

Vol 285 (6) ◽

pp. E1151-E1160 ◽

Cited By ~ 126

Author(s):

Alex W. Cohen ◽

Terry P. Combs ◽

Philipp E. Scherer ◽

Michael P. Lisanti

Keyword(s):

Insulin Receptor ◽

Insulin Signaling ◽

Cell Types ◽

Critical Discussion ◽

Signaling Cascades ◽

Membrane Microdomains ◽

Coat Proteins ◽

Caveolin 1 ◽

Unique Composition

Caveolae are specialized membrane microdomains present within the plasma membrane of the vast majority of cell types. They have a unique composition in that they are highly enriched in cholesterol, sphingolipids, and their coat proteins the caveolins (-1, -2, and -3). In recent years it has been recognized that caveolae act as signaling platforms, serving as a concentrating point for numerous signaling molecules, as well as regulating flux through many distinct signaling cascades. Although caveolae are found in a variety of cell types, they are most abundant in adipose tissue. This fact has led to the intense study of the function of these organelles in adipocytes. It has now become apparent that effective insulin signaling in the adipocyte may be strictly dependent on localization of at least two insulin-responsive elements to caveolae (insulin receptor and GLUT4), as well as on a direct functional interaction between caveolin-1 and the insulin receptor. We present a critical discussion of these recent findings.

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Role of Leishmania donovani and Its Lipophosphoglycan in CD4+ T-cell Activation-Induced Human Immunodeficiency Virus Replication

Infection and Immunity ◽

10.1128/iai.67.10.5258-5264.1999 ◽

1999 ◽

Vol 67 (10) ◽

pp. 5258-5264 ◽

Cited By ~ 30

Author(s):

Dawit Wolday ◽

Hannah Akuffo ◽

Abebech Demissie ◽

Sven Britton

Keyword(s):

Immune Activation ◽

Leishmania Donovani ◽

Mononuclear Cells ◽

Hiv Replication ◽

Activation Markers ◽

Cellular Activation ◽

Tnf Α ◽

Latently Infected ◽

Cellular Immune

ABSTRACT Chronic immune activation by coinfecting pathogens has been suggested as a cofactor in human immunodeficiency virus (HIV) disease progression, particularly in the setting of developing countries. Here, we used in vivo-infected mononuclear cells to examine the role of the protozoan parasite Leishmania donovani and its major membrane constituent, lipophosphoglycan (LPG), in mediating CD4+ T-lymphocyte activation-induced HIV replication and CD4+ T-cell death. We found that Leishmaniaantigens upregulated HIV replication in CD8-depleted peripheral blood mononuclear cells from asymptomatic HIV-infected donors compared to unstimulated cells. L. donovani-induced viral replication was associated with cellular proliferation, increased expression of the cellular immune activation markers CD25 and HLA-DR within the CD4+ subpopulation, and enhanced secretion of tumor necrosis factor alpha (TNF-α), interleukin 2 (IL-2), and IL-6. LPG induced TNF-α secretion in the absence of increased expression of cellular activation markers. Moreover, in a few cases we observed thatL. donovani induced HIV replication without significant cellular activation but with cytokine secretion. The rate of apoptosis was accelerated in these latently infected CD4+ T cells primed with Leishmania antigens compared to controls, and TNF-α production appeared to be the central event necessary for this effect. Furthermore, we demonstrate that thalidomide inhibitedLeishmania-induced virus replication coupled with abrogatedLeishmania-induced TNF-α secretion but not IL-2 or IL-6 production. Furthermore, thalidomide did not affectLeishmania-induced apoptosis. The results suggest thatLeishmania and its product, LPG, up-regulate HIV replication in latently infected cells through distinct antigen-specific and non-antigen-specific cellular immune activation mechanisms and that TNF-α secretion is pivotal in this process. The immunomodulatory role of thalidomide raises interest as a potential adjuvant to reduce HIV disease progression inLeishmania-HIV coinfected individuals.

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The role of the human cytomegalovirus UL111A gene in down-regulating CD4+ T-cell recognition of latently infected cells: implications for virus elimination during latency

Blood ◽

10.1182/blood-2008-12-197111 ◽

2009 ◽

Vol 114 (19) ◽

pp. 4128-4137 ◽

Cited By ~ 67

Author(s):

Allen K. L. Cheung ◽

David J. Gottlieb ◽

Bodo Plachter ◽

Sandra Pepperl-Klindworth ◽

Selmir Avdic ◽

...

Keyword(s):

T Cell ◽

Human Cytomegalovirus ◽

Latent Infection ◽

Interleukin 10 ◽

Cd4 T Cell ◽

Cell Recognition ◽

T Cell Recognition ◽

Latently Infected ◽

Infected Cells

AbstractThe capacity of human cytomegalovirus (HCMV) to establish and maintain a latent infection from which it can later reactivate ensures its widespread distribution in the population, but the mechanisms enabling maintenance of latency in the face of a robust immune system are poorly understood. We examined the role of the HCMV UL111A gene, which encodes homologs of the immunosuppressive cytokine interleukin-10 in the context of latent infection of myeloid progenitor cells. A UL111A deletion virus was able to establish, maintain, and reactivate from experimental latency in a manner comparable with parental virus, but major histocompatibility complex class II levels increased significantly on the surfaces of cells infected with the deletion virus. Importantly, there was an increase in both allogeneic and autologous peripheral blood mononuclear cells and CD4+ T-cell responses to UL111A deletion virus-infected myeloid progenitors, indicating that loss of the capacity to express viral interleukin-10 during latency results in latently infected cells becoming more readily recognizable by a critical arm of the immune response. The detection of a viral gene that suppresses CD4+ T-cell recognition of latently infected cells identifies an immune evasion strategy that probably enhances the capacity of HCMV to persist in a latent state within the human host.

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Cat and Mouse: HIV Transcription in Latency, Immune Evasion and Cure/Remission Strategies

Viruses ◽

10.3390/v11030269 ◽

2019 ◽

Vol 11 (3) ◽

pp. 269 ◽

Cited By ~ 7

Author(s):

Aurélie Delannoy ◽

Mikaël Poirier ◽

Brendan Bell

Keyword(s):

Immune Evasion ◽

Immune Surveillance ◽

Host Immune System ◽

Hiv Cure ◽

Major Barrier ◽

Hiv Transcription ◽

Hiv Virus ◽

Latently Infected ◽

Societal Consensus

There is broad scientific and societal consensus that finding a cure for HIV infection must be pursued. The major barrier to achieving a cure for HIV/AIDS is the capacity of the HIV virus to avoid both immune surveillance and current antiretroviral therapy (ART) by rapidly establishing latently infected cell populations, termed latent reservoirs. Here, we provide an overview of the rapidly evolving field of HIV cure/remission research, highlighting recent progress and ongoing challenges in the understanding of HIV reservoirs, the role of HIV transcription in latency and immune evasion. We review the major approaches towards a cure that are currently being explored and further argue that small molecules that inhibit HIV transcription, and therefore uncouple HIV gene expression from signals sent by the host immune response, might be a particularly promising approach to attain a cure or remission. We emphasize that a better understanding of the game of “cat and mouse” between the host immune system and the HIV virus is a crucial knowledge gap to be filled in both cure and vaccine research.

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