scholarly journals In VitroReactivation of Replication-Competent and Infectious HIV-1 by Histone Deacetylase Inhibitors

2015 ◽  
Vol 90 (4) ◽  
pp. 1858-1871 ◽  
Author(s):  
Riddhima Banga ◽  
Francesco Andrea Procopio ◽  
Matthias Cavassini ◽  
Matthieu Perreau
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Repeated Treatment ◽  
Major Barrier ◽  
Infected Cells ◽  
Memory Cd4 T Cells ◽  
Hiv 1

ABSTRACTThe existence of long-lived HIV-1-infected resting memory CD4 T cells is thought to be the primary obstacle to HIV-1 eradication. In the search for novel therapeutic approaches that may reverse HIV-1 latency, inhibitors of histone deacetylases (HDACis) have been tested to reactivate HIV-1 replication with the objective of rendering HIV-1-infected cells susceptible to elimination either by HIV-specific CD8 T cells or through virus-mediated cytopathicity. In the present study, we evaluated the efficiency of HDACis to reactivate HIV-1 replication from resting memory CD4 T cells isolated from aviremic long-term-treated HIV-1-infected subjects. We demonstrate that following prolonged/repeated treatment of resting memory CD4 T cells with HDACis, HIV-1 replication may be induced from primary resting memory CD4 T cells isolated from aviremic long-term-treated HIV-1-infected subjects. More importantly, we demonstrate that HIV-1 reactivated in the cell cultures was not only replication competent but also infectious. Interestingly, givinostat, an HDACi that has not been investigated in clinical trials, was more efficient than vorinostat, panobinostat, and romidepsin in reversing HIV-1 latencyin vitro. Taken together, these results support further evaluation of givinostat as a latency-reversing agent (LRA) in aviremic long-term-treated HIV-1-infected subjects.IMPORTANCEThe major barrier to HIV cure is the existence of long-lived latently HIV-1-infected resting memory CD4 T cells. Latently HIV-1-infected CD4 T cells are transcriptionally silent and are therefore not targeted by conventional antiretroviral therapy (ART) or the immune system. In this context, one strategy to target latently infected cells is based on pharmacological molecules that may force the virus to replicate and would therefore render HIV-1-infected cells susceptible to elimination either by HIV-specific CD8 T cells or through virus-mediated cytopathicity. In this context, we developed an experimental strategy that would allow the evaluation of latency-reversing agent (LRA) efficiencyin vitrousing primary CD4 T cells. In the present study, we demonstrate that HDACis are potent inducers of replication-competent and infectious HIV-1 in resting memory CD4 T cells of long-term ART-treated patients and identify givinostat as the most efficient LRA tested.

scholarly journals CD73+ CD127high Long-Term Memory CD4 T Cells Are Highly Proliferative in Response to Recall Antigens and Are Early Targets in HIV-1 Infection

2021 ◽  
Vol 22 (2) ◽  
pp. 912
Author(s):  
Nabila Seddiki ◽  
John Zaunders ◽  
Chan Phetsouphanh ◽  
Vedran Brezar ◽  
Yin Xu ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Significant Proportion ◽  
Long Term Memory ◽  
Ki 67 ◽  
Memory Cd4 T Cells ◽  
Hiv 1

HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5–10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6–6.4%; p = 0.002); and in chronic HIV-1 infection to 1.9% (IQR: 1.1–3%; p < 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and β7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects.

scholarly journals Elimination of SHIV Infected Cells by Combinations of Bispecific HIVxCD3 DART® Molecules

2021 ◽  
Vol 12 ◽  
Author(s):  
Marina Tuyishime ◽  
Amir Dashti ◽  
Katelyn Faircloth ◽  
Shalini Jha ◽  
Jeffrey L. Nordstrom ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Viral Envelope ◽  
Host Immune System ◽  
Infected Cells ◽  
Anti Hiv ◽  
Hiv 1

Bispecific HIVxCD3 DART molecules that co-engage the viral envelope glycoprotein (Env) on HIV-1-infected cells and the CD3 receptor on CD3+ T cells are designed to mediate the cytolysis of HIV-1-infected, Env-expressing cells. Using a novel ex vivo system with cells from rhesus macaques (RMs) infected with a chimeric Simian-Human Immunodeficiency Virus (SHIV) CH505 and maintained on ART, we tested the ability of HIVxCD3 DART molecules to mediate elimination of in vitro-reactivated CD4+ T cells in the absence or presence of autologous CD8+ T cells. HIVxCD3 DART molecules with the anti-HIV-1 Env specificities of A32 or 7B2 (non-neutralizing antibodies) or PGT145 (broadly neutralizing antibody) were evaluated individually or combined. DART molecule-mediated antiviral activity increased significantly in the presence of autologous CD8+ T cells. In this ex vivo system, the PGT145 DART molecule was more active than the 7B2 DART molecule, which was more active than the A32 DART molecule. A triple combination of the DART molecules exceeded the activity of the individual PGT145 DART molecule. Modified quantitative virus outgrowth assays confirmed the ability of the DART molecules to redirect RM CD3+ T cells to eliminate SHIV-infected RM CD4+ T cells as demonstrated by the decreased propagation of in vitro infection by the infected cells pre-incubated with DART molecules in presence of effector CD8+ T cells. While mediating cytotoxic activity, DART molecules did not increase proinflammatory cytokine production. In summary, combination of HIVxCD3 DART molecules that have broadly-neutralizing and non-neutralizing anti-HIV-1 Env specificities can leverage the host immune system for treatment of HIV-1 infection but will require appropriate reactivation of the latent reservoir.

scholarly journals Infection of CD8+CD45RO+ Memory T-Cells by HIV-1 and Their Proliferative Response

2008 ◽  
Vol 2 (1) ◽  
pp. 43-57 ◽  
Author(s):  
Naveed Gulzar ◽  
Sowyma Balasubramanian ◽  
Greg Harris ◽  
Jaime Sanchez-Dardon ◽  
Karen F.T. Copeland
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Proliferative Response ◽  
Cell Infection ◽  
Cellular Target ◽  
Potential Reservoir ◽  
Infected Cells ◽  
Hiv 1

CD8+ T-cells are involved in controlling HIV-1 infection by eliminating infected cells and secreting soluble factors that inhibit viral replication. To investigate the mechanism and significance of infection of CD8+ T-cells by HIV-1in vitro, we examined the susceptibility of these cells and their subsets to infection. CD8+ T-cells supported greater levels of replication with T-cell tropic strains of HIV-1, though viral production was lower than that observed in CD4+ T-cells. CD8+ T-cell infection was found to be productive through ELISA, RT-PCR and flow cytometric analyses. In addition, the CD8+CD45RO+ memory T-cell population supported higher levels of HIV-1 replication than CD8+CD45RA+ naïve T-cells. However, infection of CD8+CD45RO+ T-cells did not affect their proliferative response to the majority of mitogens tested. We conclude, with numerous lines of evidence detecting and measuring infection of CD8+ T-cells and their subsets, that this cellular target and potential reservoir may be central to HIV-1 pathogenesis.

scholarly journals IL-7 promotes long-term in vitro survival of unique long-lived memory subset generated from mucosal effector memory CD4+ T cells in chronic colitis mice

2013 ◽  
Vol 156 (1-2) ◽  
pp. 82-93 ◽  
Author(s):  
Masahiro Takahara ◽  
Yasuhiro Nemoto ◽  
Shigeru Oshima ◽  
Yu Matsuzawa ◽  
Takanori Kanai ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Effector Memory ◽  
Chronic Colitis ◽  
Memory Cd4 T Cells ◽  
In Vitro Survival ◽  
Memory Subset

CCR7 ligands CCL19 and CCL21 increase permissiveness of resting memory CD4+ T cells to HIV-1 infection: a novel model of HIV-1 latency

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4161-4164 ◽  
Author(s):  
Suha Saleh ◽  
Ajantha Solomon ◽  
Fiona Wightman ◽  
Miranda Xhilaga ◽  
Paul U. Cameron ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Lymphocyte Migration ◽  
Major Barrier ◽  
Memory Cd4 T Cells ◽  
Novel Model ◽  
Hiv 1

Latent HIV-1 infection of resting memory CD4+ T cells represents the major barrier to HIV-1 eradication. To determine whether the CCR7 ligands involved in lymphocyte migration can alter HIV-1 infection of resting CD4+ T cells, we infected purified resting CD4+ T cells after incubation with the chemokines CCL19 and CCL21. Incubation with CCL19 or CCL21 did not alter markers of T-cell activation or proliferation. However, after HIV-1 infection of CCL19- or CCL21-treated CD4+ T-cells, we observed low-level HIV-1 production but high concentrations of integrated HIV-1 DNA, approaching that seen in mitogen-stimulated T-cell blasts. Restimulation of CCL19-treated infected CD4+ T cells resulted in virus production consistent with establishment of postintegration latency. CCR7 ligands facilitate efficient entry of HIV-1 into resting CD4+ T cells. These studies demonstrate a unique action of the chemokines CCL19 and CCL21 and provide a novel model with which to study HIV-1 latency in vitro.

scholarly journals Th1/17 Polarization of CD4 T Cells Supports HIV-1 Persistence during Antiretroviral Therapy

2015 ◽  
Vol 89 (22) ◽  
pp. 11284-11293 ◽  
Author(s):  
Hong Sun ◽  
Dhohyung Kim ◽  
Xiaodong Li ◽  
Maja Kiselinova ◽  
Zhengyu Ouyang ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Memory Cell ◽  
Viral Reservoir ◽  
Target Cells ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTThe ability to persist long term in latently infected CD4 T cells represents a characteristic feature of HIV-1 infection and the predominant barrier to efforts aiming at viral eradication and cure. Yet, increasing evidence suggests that only small subsets of CD4 T cells with specific developmental and maturational profiles are able to effectively support HIV-1 long-term persistence. Here, we analyzed how the functional polarization of CD4 T cells shapes and structures the reservoirs of HIV-1-infected cells. We found that CD4 T cells enriched for a Th1/17 polarization had elevated susceptibilities to HIV-1 infection inex vivoassays, harbored high levels of HIV-1 DNA in persons treated with antiretroviral therapy, and made a disproportionately increased contribution to the viral reservoir relative to their contribution to the CD4 T memory cell pool. Moreover, HIV-1 DNA levels in Th1/17 cells remained stable over many years of antiretroviral therapy, resulting in a progressively increasing contribution of these cells to the viral reservoir, and phylogenetic studies suggested preferential long-term persistence of identical viral sequences during prolonged antiretroviral treatment in this cell compartment. Together, these data suggest that Th1/17 CD4 T cells represent a preferred site for HIV-1 DNA long-term persistence in patients receiving antiretroviral therapy.IMPORTANCECurrent antiretroviral therapy is very effective in suppressing active HIV-1 replication but does not fully eliminate virally infected cells. The ability of HIV-1 to persist long term despite suppressive antiretroviral combination therapy represents a perplexing aspect of HIV-1 disease pathogenesis, since most HIV-1 target cells are activated, short-lived CD4 T cells. This study suggests that CD4 T helper cells with Th1/17 polarization have a preferential role as a long-term reservoir for HIV-1 infection during antiretroviral therapy, possibly because these cells may imitate some of the functional properties traditionally attributed to stem cells, such as the ability to persist for extremely long periods of time and to repopulate their own pool size through homeostatic self-renewal. These observations support the hypothesis that HIV-1 persistence is driven by small subsets of long-lasting stem cell-like CD4 T cells that may represent particularly promising targets for clinical strategies aiming at HIV-1 eradication and cure.

Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection

Blood ◽  
2001 ◽  
Vol 98 (6) ◽  
pp. 1667-1677 ◽  
Author(s):  
Judy Lieberman ◽  
Premlata Shankar ◽  
N. Manjunath ◽  
Jan Andersson
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Short Term Exposure ◽  
Infected Cells ◽  
Hiv 1

Abstract CD8 T cells play an important role in protection and control of HIV-1 by direct cytolysis of infected cells and by suppression of viral replication by secreted factors. However, although HIV-1–infected individuals have a high frequency of HIV-1–specific CD8 T cells, viral reservoirs persist and progressive immunodeficiency generally ensues in the absence of continuous potent antiviral drugs. Freshly isolated HIV-specific CD8 T cells are often unable to lyse HIV-1–infected cells. Maturation into competent cytotoxic T lymphocytes may be blocked during the initial encounter with antigen because of defects in antigen presentation by interdigitating dendritic cells or HIV-infected macrophages. The molecular basis for impaired function is multifactorial, due to incomplete T-cell signaling and activation (in part related to CD3ζ and CD28 down-modulation), reduced perforin expression, and inefficient trafficking of HIV-specific CD8 T cells to lymphoid sites of infection. CD8 T-cell dysfunction can partially be corrected in vitro with short-term exposure to interleukin 2, suggesting that impaired HIV-specific CD4 T helper function may play a significant causal or exacerbating role. Functional defects are qualitatively different and more severe with advanced disease, when interferon γ production also becomes compromised.

scholarly journals Transcriptomic Analysis Implicates the p53 Signaling Pathway in the Establishment of HIV-1 Latency in Central Memory CD4 T Cells in an In Vitro Model

2016 ◽  
Vol 12 (11) ◽  
pp. e1006026 ◽  
Author(s):  
Cory H. White ◽  
Bastiaan Moesker ◽  
Nadejda Beliakova-Bethell ◽  
Laura J. Martins ◽  
Celsa A. Spina ◽  
...  
Keyword(s):  
T Cells ◽  
Signaling Pathway ◽  
Cd4 T Cells ◽  
In Vitro Model ◽  
P53 Signaling ◽  
Vitro Model ◽  
Memory Cd4 T Cells ◽  
P53 Signaling Pathway ◽  
Hiv 1

scholarly journals The Interplay of HIV-1 and Macrophages in Viral Persistence

2021 ◽  
Vol 12 ◽  
Author(s):  
Chynna M. Hendricks ◽  
Thaissa Cordeiro ◽  
Ana Paula Gomes ◽  
Mario Stevenson
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Viral Persistence ◽  
Vital Role ◽  
Highly Active ◽  
Antiretroviral Therapies ◽  
Memory Cd4 T Cells ◽  
Hiv 1

HIV-1 has evolved mechanisms to evade host cell immune responses and persist for lifelong infection. Latent cellular reservoirs are responsible for this persistence of HIV-1 despite the powerful effects of highly active antiretroviral therapies (HAART) to control circulating viral load. While cellular reservoirs have been extensively studied, much of these studies have focused on peripheral blood and resting memory CD4+ T cells containing latent HIV-1 provirus; however, efforts to eradicate cellular reservoirs have been stunted by reservoirs found in tissues compartments that are not easily accessible. These tissues contain resting memory CD4+ T cells and tissue resident macrophages, another latent cellular reservoir to HIV-1. Tissue resident macrophages have been associated with HIV-1 infection since the 1980s, and evidence has continued to grow regarding their role in HIV-1 persistence. Specific biological characteristics play a vital role as to why macrophages are latent cellular reservoirs for HIV-1, and in vitro and in vivo studies exhibit how macrophages contribute to viral persistence in individuals and animals on antiretroviral therapies. In this review, we characterize the role and evolutionary advantages of macrophage reservoirs to HIV-1 and their contribution to HIV-1 persistence. In acknowledging the interplay of HIV-1 and macrophages in the host, we identify reasons why current strategies are incapable of eliminating HIV-1 reservoirs and why efforts must focus on eradicating reservoirs to find a future functional cure.

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