scholarly journals Activation of Latent HIV-1 T Cell Reservoirs with a Combination of Innate Immune and Epigenetic Regulators

2019 ◽  
Vol 93 (21) ◽  
Author(s):  
Enrico Palermo ◽  
Chiara Acchioni ◽  
Daniele Di Carlo ◽  
Alessandra Zevini ◽  
Michela Muscolini ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Histone Deacetylase ◽  
Innate Immune ◽  
Viral Reservoir ◽  
Hiv Eradication ◽  
Shock And Kill ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT The presence of T cell reservoirs in which human immunodeficiency virus (HIV) establishes latency by integrating into the host genome represents a major obstacle to an HIV cure and has prompted the development of strategies aimed at the eradication of HIV from latently infected cells. The “shock-and-kill” strategy is one of the most pursued approaches to the elimination of viral reservoirs. Although several latency-reversing agents (LRAs) have shown promising reactivation activity, they have failed to eliminate the cellular reservoir. In this study, we evaluated a novel immune system-mediated approach to clearing the HIV reservoir, based on a combination of innate immune stimulation and epigenetic reprogramming. The combination of the STING agonist cGAMP (cyclic GMP-AMP) and the FDA-approved histone deacetylase inhibitor resminostat resulted in a significant increase in HIV proviral reactivation and specific apoptosis in HIV-infected cells in vitro. Reductions in the proportion of HIV-harboring cells and the total amount of HIV DNA were also observed in CD4+ central memory T (TCM) cells, a primary cell model of latency, where resminostat alone or together with cGAMP induced high levels of selective cell death. Finally, high levels of cell-associated HIV RNA were detected ex vivo in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells from individuals on suppressive antiretroviral therapy (ART). Although synergism was not detected in PBMCs with the combination, viral RNA expression was significantly increased in CD4+ T cells. Collectively, these results represent a promising step toward HIV eradication by demonstrating the potential of innate immune activation and epigenetic modulation for reducing the viral reservoir and inducing specific death of HIV-infected cells. IMPORTANCE One of the challenges associated with HIV-1 infection is that despite antiretroviral therapies that reduce HIV-1 loads to undetectable levels, proviral DNA remains dormant in a subpopulation of T lymphocytes. Numerous strategies to clear residual virus by reactivating latent virus and eliminating the reservoir of HIV-1 (so-called “shock-and-kill” strategies) have been proposed. In the present study, we use a combination of small molecules that activate the cGAS-STING antiviral innate immune response (the di-cyclic nucleotide cGAMP) and epigenetic modulators (histone deacetylase inhibitors) that induce reactivation and HIV-infected T cell killing in cell lines, primary T lymphocytes, and patient samples. These studies represent a novel strategy for HIV eradication by reducing the viral reservoir and inducing specific death of HIV-infected cells.

scholarly journals Reactivation Kinetics of HIV-1 and Susceptibility of Reactivated Latently Infected CD4+T Cells to HIV-1-Specific CD8+T Cells

2015 ◽  
Vol 89 (18) ◽  
pp. 9631-9638 ◽  
Author(s):  
Victoria E. K. Walker-Sperling ◽  
Valerie J. Cohen ◽  
Patrick M. Tarwater ◽  
Joel N. Blankson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Time Frame ◽  
Virus Release ◽  
Latently Infected ◽  
Shock And Kill ◽  
Infected Cells ◽  
Kinetics Of ◽  
Hiv 1

ABSTRACTThe “shock and kill” model of human immunodeficiency virus type 1 (HIV-1) eradication involves the induction of transcription of HIV-1 genes in latently infected CD4+T cells, followed by the elimination of these infected CD4+T cells by CD8+T cells or other effector cells. CD8+T cells may also be needed to control the spread of new infection if residual infected cells are present at the time combination antiretroviral therapy (cART) is discontinued. In order to determine the time frame needed for CD8+T cells to effectively prevent the spread of HIV-1 infection, we examined the kinetics of HIV transcription and virus release in latently infected cells reactivatedex vivo. Isolated resting, primary CD4+T cells from HIV-positive (HIV+) subjects on suppressive regimens were found to upregulate cell-associated HIV-1 mRNA within 1 h of stimulation and produce extracellular virus as early as 6 h poststimulation. In spite of the rapid kinetics of virus production, we show that CD8+T cells from 2 out of 4 viremic controllers were capable of effectively eliminating reactivated autologous CD4+cells that upregulate cell-associated HIV-1 mRNA. The results have implications for devising strategies to prevent rebound viremia due to reactivation of rare latently infected cells that persist after potentially curative therapy.IMPORTANCEA prominent HIV-1 cure strategy termed “shock and kill” involves the induction of HIV-1 transcription in latently infected CD4+T cells with the goal of elimination of these cells by either the cytotoxic T lymphocyte response or other immune cell subsets. However, the cytotoxic T cell response may also be required after curative treatment if residual latently infected cells remain. The kinetics of HIV-1 reactivation indicate rapid upregulation of cell-associated HIV-1 mRNA and a 5-h window between transcription and virus release. Thus, HIV-specific CD8+T cell responses likely have a very short time frame to eliminate residual latently infected CD4+T cells that become reactivated after discontinuation of antiretroviral therapy following potentially curative treatment strategies.

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 Chimeric Antigen Receptor T Cells Guided by the Single-Chain Fv of a Broadly Neutralizing Antibody Specifically and Effectively Eradicate Virus Reactivated from Latency in CD4 + T Lymphocytes Isolated from HIV-1-Infected Individuals Receiving Suppressive Combined Antiretroviral Therapy

2016 ◽  
Vol 90 (21) ◽  
pp. 9712-9724 ◽  
Author(s):  
Bingfeng Liu ◽  
Fan Zou ◽  
Lijuan Lu ◽  
Cancan Chen ◽  
Dalian He ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
T Lymphocytes ◽  
Chimeric Antigen Receptor ◽  
Car T Cells ◽  
Combined Antiretroviral Therapy ◽  
Car T ◽  
Infected Cells ◽  
Hiv 1

ABSTRACT Despite the advent of combined antiretroviral therapy (cART), the persistence of viral reservoirs remains a major barrier to curing human immunodeficiency virus type 1 (HIV-1) infection. Recently, the shock and kill strategy, by which such reservoirs are eradicated following reactivation of latent HIV-1 by latency-reversing agents (LRAs), has been extensively practiced. It is important to reestablish virus-specific and reliable immune surveillance to eradicate the reactivated virus-harboring cells. In this report, we attempted to reach this goal by using newly developed chimeric antigen receptor (CAR)-T cell technology. To generate anti-HIV-1 CAR-T cells, we connected the single-chain variable fragment of the broadly neutralizing HIV-1-specific antibody VRC01 to a third-generation CAR moiety as the extracellular and intracellular domains and subsequently transduced this into primary CD8 + T lymphocytes. We demonstrated that the resulting VC-CAR-T cells induced T cell-mediated cytolysis of cells expressing HIV-1 Env proteins and significantly inhibited HIV-1 rebound after removal of antiviral inhibitors in a viral infectivity model in cell culture that mimics the termination of the cART in the clinic. Importantly, the VC-CAR-T cells also effectively induced the cytolysis of LRA-reactivated HIV-1-infected CD4 + T lymphocytes isolated from infected individuals receiving suppressive cART. Our data demonstrate that the special features of genetically engineered CAR-T cells make them a particularly suitable candidate for therapeutic application in efforts to reach a functional HIV cure. IMPORTANCE The presence of latently infected cells remains a key obstacle to the development of a functional HIV-1 cure. Reactivation of dormant viruses is possible with latency-reversing agents, but the effectiveness of these compounds and the subsequent immune response require optimization if the eradication of HIV-1-infected cells is to be achieved. Here, we describe the use of a chimeric antigen receptor, comprised of T cell activation domains and a broadly neutralizing antibody, VRC01, targeting HIV-1 to treat the infected cells. T cells expressing this construct exerted specific cytotoxic activity against wild-type HIV-1-infected cells, resulting in a dramatic reduction in viral rebound in vitro , and showed persistent effectiveness against reactivated latently infected T lymphocytes from HIV-1 patients receiving combined antiretroviral therapy. The methods used in this study constitute an improvement over existing CD4-based CAR-T technology and offer a promising approach to HIV-1 immunotherapy.

scholarly journals Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8+T Cells

2018 ◽  
Vol 93 (3) ◽  
Author(s):  
Abena K. R. Kwaa ◽  
Chloe A. G. Talana ◽  
Joel N. Blankson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Effector Cell ◽  
Cell Function ◽  
Nk Cell ◽  
Suppressive Capacity ◽  
Short Course ◽  
Shock And Kill ◽  
Hiv 1

ABSTRACTCurrent shock-and-kill strategies for the eradication of the HIV-1 reservoir have resulted in blips of viremia but not in a decrease in the size of the latent reservoir in patients on suppressive antiretroviral therapy (ART). This discrepancy could potentially be explained by an inability of the immune system to kill HIV-1-infected cells following the reversal of latency. Furthermore, some studies have suggested that certain latency-reversing agents (LRAs) may inhibit CD8+T cell and natural killer (NK) cell responses. In this study, we tested the hypothesis that alpha interferon (IFN-α) could improve the function of NK cells from chronic progressors (CP) on ART. We show here that IFN-α treatment enhanced cytokine secretion, polyfunctionality, degranulation, and the cytotoxic potential of NK cells from healthy donors (HD) and CP. We also show that this cytokine enhanced the viral suppressive capacity of NK cells from HD and elite controllers or suppressors. Furthermore, IFN-α enhanced global CP CD8+T cell cytokine responses and the suppressive capacity of ES CD8+T cells. Our data suggest that IFN-α treatment may potentially be used as an immunomodulatory agent in HIV-1 cure strategies.IMPORTANCEData suggest that HIV+individuals unable to control infection fail to do so due to impaired cytokine production and/cytotoxic effector cell function. Consequently, the success of cure agendas such as the shock-and-kill strategy will probably depend on enhancing patient effector cell function. In this regard, NK cells are of particular interest since they complement the function of CD8+T cells. Here, we demonstrate the ability of short-course alpha interferon (IFN-α) treatments to effectively enhance such effector functions in chronic progressor NK cells without inhibiting their general CD8+T cell function. These results point to the possibility of exploring such short-course IFN-α treatments for the enhancement of effector cell function in HIV+patients in future cure strategies.

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 Vδ1 T lymphocytes producing IFN-γ and IL-17 are expanded in HIV-1–infected patients and respond to Candida albicans

Blood ◽  
2009 ◽  
Vol 113 (26) ◽  
pp. 6611-6618 ◽  
Author(s):  
Daniela Fenoglio ◽  
Alessandro Poggi ◽  
Silvia Catellani ◽  
Florinda Battaglia ◽  
Alessandra Ferrera ◽  
...  
Keyword(s):  
T Cells ◽  
Candida Albicans ◽  
T Cell ◽  
T Lymphocytes ◽  
Receptor Expression ◽  
Interleukin 17 ◽  
Γδ T Cell ◽  
Healthy Donors ◽  
Ifn Γ ◽  
Hiv 1

AbstractIn early HIV-1 infection, Vδ1 T lymphocytes are increased in peripheral blood and this is related to chemokine receptor expression, chemokine response, and recirculation. Herein we show that, at variance with healthy donors, in HIV-1–infected patients ex vivo–isolated Vδ1 T cells display cytoplasmic interferon-γ (IFN-γ). Interestingly, these cells coexpress cytoplasmic interleukin-17 (IL-17), and bear the CD27 surface marker of the memory T-cell subset. Vδ1 T cells, isolated from either patients or healthy donors, can proliferate and produce IFN-γ and IL-17 in response to Candida albicans in vitro, whereas Vδ2 T cells respond with proliferation and IFN-γ/IL-17 production to mycobacterial or phosphate antigens. These IFN-γ/IL-17 double-producer γδ T cells express the Th17 RORC and the Th1 TXB21 transcription factors and bear the CCR7 homing receptor and the CD161 molecule that are involved in γδ T-cell transendothelial migration. Moreover, Vδ1 T cells responding to C albicans express the chemokine receptors CCR4 and CCR6. This specifically equipped circulating memory γδ T-cell population might play an important role in the control of HIV-1 spreading and in the defense against opportunistic infections, possibly contributing to compensate for the impairment of CD4+ T cells.

IL15 Enhances Proliferation and Effector Function of Antigen-Specific Cytotoxic T Lymphocytes (CTLs) and Mitigates the Suppressive Action of Regulatory T Cells (Tregs).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4088-4088
Author(s):  
Serena Kimi Perna ◽  
Biagio De Angelis ◽  
Daria Pagliara ◽  
Lan Zhan ◽  
Cliona M Rooney ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Tumor Cells ◽  
Residual Tumor ◽  
Facs Analysis ◽  
Activated T Cells ◽  
Specific Ctls ◽  
Infected Cells ◽  
And Function

Abstract Abstract 4088 Poster Board III-1023 Although adoptive transfer of antigen-specific CTLs is generally safe and can be clinically effective for the treatment of several malignancies, the administration of stimulatory cytokines may be required to sustain their long-term growth and persistence in vivo. IL2, a γ-chain T-cell growth cytokine, has been used clinically, but is associated with significant toxicities. In addition, IL2 supports the expansion and function of Tregs, counterbalancing its stimulatory effects on CTLs and favoring the establishment of an immune-protected microenvironment for cancer. IL15, like IL2, is a γ-chain cytokine capable of sustaining the expansion and function of effector T cells. We have explored whether this cytokine also shares with IL2 an unwanted stimulatory effect on Tregs. Naturally occurring Tregs (CD4+CD25bright) were isolated from buffy coat preparations from healthy volunteers (mean of Treg recovery: 0.7% ± 0.05% of the starting population of mononuclear cells). The suppressive function of isolated Tregs was confirmed by their ability to inhibit the proliferation of activated T lymphocytes labeled with carboxyfluorescin diacetate succinimidyl ester (CFSE) using FACS analysis to measure CFSE dilution after 5-6 days of culture (activated T cell:Treg ratio 1:1). The proliferation of activated T cells in the presence of Tregs was significantly reduced (28%±5%) as compared to activated T cells cultured in the presence of control CD4+CD25– T cells (59%±5%) (p<0.05). Following addition of IL15 (2.5 ng/mL), however, proliferation of activated T cells continued even in the presence of Tregs (83%±5% plus IL15 without Tregs vs. 80%±5% plus IL15 and Tregs) (p=0.9), suggesting that this cytokine mitigates the immunosuppressive effects of Tregs. We then analyzed whether Tregs affected the anti-tumor activity of antigen-specific CTLs. We used our Epstein-Barr-Virus-(EBV)-specific CTLs as tumor model. EBV-CTLs were co-cultured with EBV-infected cells (LCLs) (CTL:LCL ratio 1:2). Residual tumor cells were enumerated by FACS analysis after 5-7 days of culture. In the absence of exogenous IL-15, EBV-CTLs failed to eliminate EBV-infected cells (residual LCLs: 37%±8%), while the addition of IL15 (2.5 ng/mL) increased the anti-tumor effect of CTLs, so that only 4%±1% tumor cells were detectable at the end of the culture. We then explored the effects of adding Treg to the cultures (Treg:CTL ratio 1:1). The percentage of tumor cells increased rather than decreased by day 5-7 when CTLs were cultured with Tregs in the absence of IL15 (residual tumor cells from 37%±8% in the absence of Tregs to 53%±9% in the presence of Tregs) (p<0.05). When IL15 was added, Treg were more limited in their ability to inhibit T effector cells, so that residual tumor cells were 4%±1% and 11%±3% % in the absence or in the presence of Tregs, respectively. To discover if IL15 has a direct effect on Tregs, we analyzed STAT5 phosphorylation after exposing Tregs to the cytokine. We found that this molecule was phosphorylated in 47%±18% of Tregs 15 minutes after exposure to IL15 (2.5 ng/mL). This effect was mediated by the specific interaction of the cytokine with its own receptor, as no phosphorylation occurred when Treg cells were pre-incubated with an IL-15Rα blocking antibody. This action on Tregs notwithstanding, IL15 stimulation did not modulate Treg inhibitory function, since these cells, even after exposure to IL15 (2.5 ng/mL) for 3-5 days, continued to significantly inhibit the proliferation of T lymphocytes activated in the absence of IL-15 (74%±17% inhibition). Hence, IL15 enhance the proliferative and anti-tumor effects of antigen-specific CTLs, and these effects are not impaired by the presence of Tregs. Administration of IL15 may therefore benefit patients receiving adoptive T cell therapies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Activation of virus replication after vaccination of HIV-1-infected individuals.

1995 ◽  
Vol 182 (6) ◽  
pp. 1727-1737 ◽  
Author(s):  
S I Staprans ◽  
B L Hamilton ◽  
S E Follansbee ◽  
T Elbeik ◽  
P Barbosa ◽  
...  
Keyword(s):  
T Cells ◽  
Steady State ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Vaccine Antigens ◽  
Steady State Levels ◽  
Hiv 1

Little is known about the factors that govern the level of HIV-1 replication in infected individuals. Recent studies (using potent antiviral drugs) of the kinetics of HIV-1 replication in vivo have demonstrated that steady-state levels of viremia are sustained by continuous rounds of de novo infection and the associated rapid turnover of CD4+ T lymphocytes. However, no information is available concerning the biologic variables that determine the size of the pool of T cells that are susceptible to virus infection or the amount of virus produced from infected cells. Furthermore, it is not known whether all CD4+ T lymphocytes are equally susceptible to HIV-1 infection at a given time or whether the infection is focused on cells of a particular state of activation or antigenic specificity. Although HIV-1 replication in culture is known to be greatly facilitated by T cell activation, the ability of specific antigenic stimulation to augment HIV-1 replication in vivo has not been studied. We sought to determine whether vaccination of HIV-1-infected adults leads to activation of virus replication and the targeting of vaccine antigen-responsive T cells for virus infection and destruction. Should T cell activation resulting from exposure to environmental antigens prove to be an important determinant of the steady-state levels of HIV-1 replication in vivo and lead to the preferential loss of specific populations of CD4+ T lymphocytes, it would have significant implications for our understanding of and therapeutic strategies for HIV-1 disease. To begin to address these issues, HIV-1-infected individuals and uninfected controls were studied by measurement of immune responses to influenza antigens and quantitation of virion-associated plasma HIV-1 RNA levels at baseline and at intervals after immunization with the trivalent influenza vaccine. Influenza vaccination resulted in readily demonstrable but transient increases in plasma HIV-1 RNA levels, indicative of activation of viral replication, in HIV-1-infected individuals with preserved ability to immunologically respond to vaccine antigens. Activation of HIV-1 replication by vaccination was more often seen and of greater magnitude in individuals who displayed a T cell proliferative response to vaccine antigens at baseline and in those who mounted a significant serologic response after vaccination. The fold increase in viremia, as well as the rates of increase of HIV-1 in plasma after vaccination and rates of viral decline after peak viremia, were higher in individuals with higher CD4+ T cell counts.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

scholarly journals Early antiretroviral therapy in neonates with HIV-1 infection restricts viral reservoir size and induces a distinct innate immune profile

2019 ◽  
Vol 11 (520) ◽  
pp. eaax7350 ◽  
Author(s):  
Pilar Garcia-Broncano ◽  
Shivaali Maddali ◽  
Kevin B. Einkauf ◽  
Chenyang Jiang ◽  
Ce Gao ◽  
...  
Keyword(s):  
T Cell ◽  
Antiretroviral Therapy ◽  
Evolutionary Dynamics ◽  
T Cell Response ◽  
Innate Immune ◽  
Viral Reservoir ◽  
Viral Control ◽  
Immune Profile ◽  
Treatment Interruptions ◽  
Hiv 1

Neonatal HIV-1 infection is associated with rapidly progressive and frequently fatal immune deficiency if left untreated. Immediate institution of antiretroviral therapy (ART), ideally within hours after birth, may restrict irreversible damage to the developing neonatal immune system and possibly provide opportunities for facilitating drug-free viral control during subsequent treatment interruptions. However, the virological and immunological effects of ART initiation within hours after delivery have not been systematically investigated. We examined a unique cohort of neonates with HIV-1 infection from Botswana who started ART shortly after birth and were followed longitudinally for about 2 years in comparison to control infants started on treatment during the first year after birth. We demonstrate multiple clear benefits of rapid antiretroviral initiation, including an extremely small reservoir of intact proviral sequences, a reduction in abnormal T cell immune activation, a more polyfunctional HIV-1–specific T cell response, and an innate immune profile that displays distinct features of improved antiviral activity and is associated with intact proviral reservoir size. Together, these data offer rare insight into the evolutionary dynamics of viral reservoir establishment in neonates and provide strong empirical evidence supporting the immediate initiation of ART for neonates with HIV-1 infection.

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