HIV replication in conjunction with granzyme B production by CCR5+ memory CD4 T cells: Implications for bystander cell and tissue pathologies

Tissue resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8 TRM, there has been recently an increased interest in defining the phenotype and the role of CD4 TRM in diseases. Circulating CD4 T cells seed tissue CD4 TRM, but there also appears to be an equilibrium between CD4 TRM and blood CD4 T cells. CD4 TRM are more mobile than CD8 TRM, usually localized deeper within the dermis/lamina propria and yet may exhibit synergy with CD8 TRM in disease control. This has been demonstrated in herpes simplex infections in mice. In human recurrent herpes infections, both CD4 and CD8 TRM persisting between lesions may control asymptomatic shedding through interferon gamma secretion, although this has been more clearly shown for CD8 T cells. The exact role of the CD4/CD8 TRM axis in the trigeminal ganglia and/or cornea in controlling recurrent herpetic keratitis is unknown. In HIV, CD4 TRM have now been shown to be a major target for productive and latent infection in cervix. In HSV and HIV co-infections, CD4 TRM persisting in the dermis support HIV replication. Further understanding of the role of CD4 TRM and their induction by vaccines may help control sexual transmission by both viruses.

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Pregnancy Gestation Impacts on HIV-1-Specific Granzyme B Response and Central Memory CD4 T Cells

Frontiers in Immunology ◽

10.3389/fimmu.2020.00153 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 1

Author(s):

Alexander T. H. Cocker ◽

Nishel M. Shah ◽

Inez Raj ◽

Sarah Dermont ◽

Waheed Khan ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Granzyme B ◽

Central Memory ◽

Memory Cd4 T Cells ◽

Hiv 1

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Granzyme B secretion by human memory CD4 T cells is less strictly regulated compared to memory CD8 T cells

BMC Immunology ◽

10.1186/s12865-014-0036-1 ◽

2014 ◽

Vol 15 (1) ◽

Cited By ~ 23

Author(s):

Lin Lin ◽

Jacob Couturier ◽

Xiaoying Yu ◽

Miguel A Medina ◽

Claudia A Kozinetz ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Granzyme B ◽

Human Memory ◽

Memory Cd8 T Cells ◽

Memory Cd4 T Cells

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Blind Uneven Proliferation of CD4+ T cells During Primary Infection Generates the Majority of the HIV Reservoir

10.1101/2020.04.06.20053231 ◽

2020 ◽

Author(s):

Florencia A. T. Boshier ◽

Daniel B. Reeves ◽

Elizabeth R. Duke ◽

David A. Swan ◽

Martin Prlic ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Cellular Proliferation ◽

Chromosomal Dna ◽

Hiv Replication ◽

Hiv Reservoir ◽

Viral Spread ◽

Hiv Dna ◽

Latently Infected ◽

Memory Cd4 T Cells

AbstractThe HIV reservoir is a population of 1-10 million anatomically dispersed, latently infected memory CD4+ T cells in which an HIV DNA molecule is quiescently integrated into human chromosomal DNA. When antiretroviral therapy (ART) is stopped and HIV replication initiates in one of these cells, systemic viral spread resumes, rekindling progression to AIDS. Therefore, HIV latency prevents cure. The HIV reservoir contains clones: identical HIV sequences that are integrated within identical human chromosomal DNA locations. The presence of these clones demonstrates that proliferation of CD4+ T cells sustains infection despite ART. The reservoir has a precise structure consisting of a small number of large clones and a large number of small clones. However, the mechanisms leading to this structure have not been identified. We developed a mathematical model that recapitulates the profound depletion and brisk recovery of CD4+ T cells, reservoir creation, and viral load trajectory during primary HIV infection. We extended the model to simulate stochastically individual HIV reservoir clones and identified that uneven proliferation among clones during recovery from CD4+ lymphopaenia is sufficient to explain the observed clonal reservoir distribution. We project that within one month of infection 75-95% of reservoir cells are generated from cellular proliferation rather than denovo viral infection. Recent detection of HIV infected clones during the first 5 weeks of infection support our model’s predictions.

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Regulation of cyclin T1 during HIV replication and latency establishment in human memory CD4 T cells

Virology Journal ◽

10.1186/s12985-019-1128-6 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 4

Author(s):

Jacob Couturier ◽

Aaron F. Orozco ◽

Hongbing Liu ◽

Sona Budhiraja ◽

Edward B. Siwak ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Human Memory ◽

Hiv Replication ◽

Cyclin T1 ◽

Memory Cd4 T Cells

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The Role of Tissue Resident Memory CD4 T Cells in Herpes Simplex Viral and HIV Infection

Viruses ◽

10.3390/v13030359 ◽

2021 ◽

Vol 13 (3) ◽

pp. 359

Author(s):

Thomas R. O’Neil ◽

Kevin Hu ◽

Naomi R. Truong ◽

Sana Arshad ◽

Barbara L. Shacklett ◽

...

Keyword(s):

T Cells ◽

Herpes Simplex ◽

Cd4 T Cells ◽

Sexual Transmission ◽

Trigeminal Ganglia ◽

Hiv Replication ◽

Recurrent Herpes ◽

Resident Memory T Cells ◽

Memory Cd4 T Cells

Tissue-resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8+ TRM, there has recently been increased interest in defining the phenotype and the role of CD4+ TRM in diseases. Circulating CD4+ T cells seed CD4+ TRM, but there also appears to be an equilibrium between CD4+ TRM and blood CD4+ T cells. CD4+ TRM are more mobile than CD8+ TRM, usually localized deeper within the dermis/lamina propria and yet may exhibit synergy with CD8+ TRM in disease control. This has been demonstrated in herpes simplex infections in mice. In human recurrent herpes infections, both CD4+ and CD8+ TRM persisting between lesions may control asymptomatic shedding through interferon-gamma secretion, although this has been more clearly shown for CD8+ T cells. The exact role of the CD4+/CD8+ TRM axis in the trigeminal ganglia and/or cornea in controlling recurrent herpetic keratitis is unknown. In HIV, CD4+ TRM have now been shown to be a major target for productive and latent infection in the cervix. In HSV and HIV co-infections, CD4+ TRM persisting in the dermis support HIV replication. Further understanding of the role of CD4+ TRM and their induction by vaccines may help control sexual transmission by both viruses.

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Naive CD4 T cells inhibit CD28-costimulated R5 HIV replication in memory CD4 T cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.211205098 ◽

2001 ◽

Vol 98 (20) ◽

pp. 11644-11649 ◽

Cited By ~ 12

Author(s):

M. Mengozzi ◽

M. Malipatlolla ◽

S. C. De Rosa ◽

L. A. Herzenberg ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Hiv Replication ◽

Memory Cd4 T Cells

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Endothelial cells promote productive HIV infection of resting CD4+ T cells by an integrin-mediated cell adhesion-dependent mechanism

10.1101/2020.06.29.177402 ◽

2020 ◽

Author(s):

Catherine M. Card ◽

Bernard Abrenica ◽

Lyle R. McKinnon ◽

T. Blake Ball ◽

Ruey-Chyi Su

Keyword(s):

T Cells ◽

Endothelial Cells ◽

Hiv Infection ◽

Cd4 T Cells ◽

Cell Trafficking ◽

Hiv Replication ◽

Hiv Susceptibility ◽

Hiv Acquisition ◽

Memory Cd4 T Cells

AbstractResting CD4+ T cells do not support HIV replication in vitro, yet are primary targets of early HIV infection events in vivo. There is an established role for factors in the tissue microenvironment, including endothelial cells, in enhancing the susceptibility of resting CD4+ T cells to productive infection, yet the mechanisms behind this are not well understood. Endothelial cells facilitate immune cell trafficking throughout the body. Cell adhesion molecules expressed by endothelial cells engage integrins on activated and memory T cells and mediate transmigration into inflamed tissues. These cell trafficking pathways have overlapping roles in facilitating HIV replication but their relevance to endothelial cell-mediated enhancement of HIV susceptibility in resting CD4+ T cells has not previously been examined. We used flow cytometry to characterize the phenotype resting CD4+ T cells that became productively infected when exposed to HIV in the presence of endothelial cells. Infected CD4+ T cells were primarily central memory cells enriched for high expression of the integrins LFA-1 and VLA-4 and had variable expression of α4β7, CCR6 and CD69. Blocking LFA-1 and VLA-4 on resting CD4+ T cells abrogated infection in the co-culture model, indicating that engagement of these integrins is essential for enhancement of resting CD4+ T cell HIV susceptibility by endothelial cells. Cellular activation of CD4+ T cells did not appear to be the primary mechanism enabling HIV replication since only a small proportion of resting CD4+ T cells became activated over the course of the co-culture and fewer than half of infected cells had an activated phenotype. The demonstration that endothelial cells enhance the cellular HIV susceptibility of resting memory CD4+ T cells through cell trafficking pathways engaged during the transmigration of memory T cells into inflamed tissues highlights the physiological relevance of these findings for HIV acquisition and opportunities for intervention.Author SummaryHIV acquisition risk per coital act is relatively low, but this risk is amplified by various behavioural and biological variables. Genital inflammation is a key biological variable associated with increased risk of HIV acquisition, but the mechanisms driving this are incompletely understood. Inflammation is a complex process, with direct effects on HIV target cells as well as the tissue in which those cells reside and encounter virus. The first HIV target cells in vivo are resting memory CD4+ T cells, yet these cells are do not support viral replication when purified and exposed to HIV in vitro. Rather, signals from tissue microenvironment are required to support viral replication within resting memory CD4+ T cells. Endothelial cells line tissue vasculature and guide immune cell trafficking to inflamed tissues through engagement of integrins by endothelial-expressed cell adhesion molecules. We show here that these same cell-trafficking pathways enable endothelial cells to promote HIV replication within resting memory CD4+ T cells in vitro. Blockade of integrins on resting memory CD4+ T cells prevented endothelial enhancement of HIV infection. These findings further our understanding of the determinants of cellular susceptibility to HIV infection and offer a potential mechanism by which inflammation promotes HIV acquisition.

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Prime, Shock, and Kill: Priming CD4 T Cells from HIV Patients with a BCL-2 Antagonist before HIV Reactivation Reduces HIV Reservoir Size

Journal of Virology ◽

10.1128/jvi.03179-15 ◽

2016 ◽

Vol 90 (8) ◽

pp. 4032-4048 ◽

Cited By ~ 45

Author(s):

Nathan W. Cummins ◽

Amy M. Sainski ◽

Haiming Dai ◽

Sekar Natesampillai ◽

Yuan-Ping Pang ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Ex Vivo ◽

Hiv Protease ◽

Hiv Replication ◽

Hiv Patients ◽

Hiv Reservoir ◽

Hiv Dna ◽

Proapoptotic Protein ◽

Memory Cd4 T Cells

ABSTRACTUnderstanding how some HIV-infected cells resist the cytotoxicity of HIV replication is crucial to enabling HIV cure efforts. HIV killing of CD4 T cells that replicate HIV can involve HIV protease-mediated cleavage of procaspase 8 to generate a fragment (Casp8p41) that directly binds and activates the mitochondrial proapoptotic protein BAK. Here, we demonstrate that Casp8p41 also binds with nanomolar affinity to the antiapoptotic protein Bcl-2, which sequesters Casp8p41 and prevents apoptosis. Further, we show that central memory CD4 T cells (TCM) from HIV-infected individuals have heightened expression of BCL-2 relative to procaspase 8, possibly explaining the persistence of HIV-infected TCMdespite generation of Casp8p41. Consistent with this hypothesis, the selective BCL-2 antagonist venetoclax induced minimal killing of uninfected CD4 T cells but markedly increased the death of CD4 T cells and diminished cell-associated HIV DNA when CD4 T cells from antiretroviral therapy (ART)-suppressed HIV patients were induced with αCD3/αCD28 to reactivate HIVex vivo. Thus, priming CD4 T cells from ART suppressed HIV patients with a BCL-2 antagonist, followed by HIV reactivation, achieves reductions in cell-associated HIV DNA, whereas HIV reactivation alone does not.IMPORTANCEHIV infection is incurable due to a long-lived reservoir of HIV+memory CD4 T cells, and no clinically relevant interventions have been identified that reduce the number of these HIV DNA-containing cells. Since postintegration HIV replication can result in HIV protease generation of Casp8p41, which activates BAK, causing infected CD4 T cell death, we sought to determine whether this occurs in memory CD4 T cells. Here, we demonstrate that memory CD4 T cells can generate Casp8p41 and yet are intrinsically resistant to death induced by diverse stimuli, including Casp8p41. Furthermore, BCL-2 expression is relatively increased in these cells and directly binds and inhibits Casp8p41's proapoptotic effects. Antagonizing BCL-2 with venetoclax derepresses this antagonism, resulting in death, preferentially in HIV DNA containing cells, since only these cells generate Casp8p41. Thus, BCL-2 antagonism is a clinically relevant intervention with the potential to reduce HIV reservoir size in patients.

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