HIV Type-1 Latency: Targeted Induction of Proviral Reservoirs

2009 ◽  
Vol 19 (5) ◽  
pp. 177-187 ◽  
Author(s):  
Jason D Graci ◽  
Joseph M Colacino ◽  
Stuart W Peltz ◽  
Joseph P Dougherty ◽  
Zhengxian Gu
Keyword(s):  
T Cells ◽  
Highly Active Antiretroviral Therapy ◽  
Current Knowledge ◽  
Therapeutic Agents ◽  
Viral Reactivation ◽  
Highly Active ◽  
Hiv Type 1 ◽  
Latent Hiv ◽  
Hiv 1

HIV type-1 (HIV-1) can establish a state of latency in infected patients, most notably in resting CD4+ T-cells. This long-lived reservoir allows for rapid re-emergence of viraemia upon cessation of highly active antiretroviral therapy, even after extensive and seemingly effective treatment. Successful depletion of such latent reservoirs is probably essential to ‘cure’ HIV-1 infection and will require therapeutic agents that can specifically and efficiently act on cells harbouring latent HIV-1 provirus. The mechanisms underlying HIV-1 latency are not well characterized, and it is becoming clear that numerous factors, both cell- and virus-derived, are involved in the maintenance of proviral latency. The interplay of these various factors in the context of viral reactivation is still poorly understood. In this article, we review the current knowledge regarding the mechanisms underlying maintenance of HIV-1 latency, both transcriptional and post-transcriptional, with a focus on potential targets that might be exploited to therapeutically purge latent proviral reservoirs from infected patients.

scholarly journals Analysis of Human Immunodeficiency Virus Type 1 Transcriptional Elongation in Resting CD4+ T Cells In Vivo

2004 ◽  
Vol 78 (17) ◽  
pp. 9105-9114 ◽  
Author(s):  
Kara G. Lassen ◽  
Justin R. Bailey ◽  
Robert F. Siliciano
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Antiretroviral Therapy ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Highly Active Antiretroviral Therapy ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT A stable latent reservoir for human immunodeficiency virus type 1 (HIV-1) in resting memory CD4+ T cells presents a barrier to eradication of the infection even in patients on highly active antiretroviral therapy. Potential mechanisms for latency include inaccessibility of the integrated viral genome, absence of key host transcription factors, premature termination of HIV-1 RNAs, and abnormal splicing patterns. To differentiate among these mechanisms, we isolated extremely pure populations of resting CD4+ T cells from patients on highly active antiretroviral therapy. These cells did not produce virus but retained the capacity to do so if appropriately stimulated. Products of HIV-1 transcription were examined in purified resting CD4+ T cells. Although short, prematurely terminated HIV-1 transcripts have been suggested as a marker for latently infected cells, the production of short transcripts had not been previously demonstrated in purified populations of resting CD4+ T cells. By separating RNA into polyadenylated and nonpolyadenylated fractions, we showed that resting CD4+ T cells from patients on highly active antiretroviral therapy produce abortive transcripts that lack a poly(A) tail and that terminate prior to nucleotide 181. Short transcripts dominated the pool of total HIV-1 transcripts in resting CD4+ T cells. Processive, polyadenylated HIV-1 mRNAs were also present at a low level. Both unspliced and multiply spliced forms were found. Taken together, these results show that the nonproductive nature of the infection in resting CD4+ T cells from patients on highly active antiretroviral therapy is not due to absolute blocks at the level of either transcriptional initiation or elongation but rather relative inefficiencies at multiple steps.

scholarly journals Severe CD4+ T-Cell Depletion in Gut Lymphoid Tissue during Primary Human Immunodeficiency Virus Type 1 Infection and Substantial Delay in Restoration following Highly Active Antiretroviral Therapy

2003 ◽  
Vol 77 (21) ◽  
pp. 11708-11717 ◽  
Author(s):  
Moraima Guadalupe ◽  
Elizabeth Reay ◽  
Sumathi Sankaran ◽  
Thomas Prindiville ◽  
Jason Flamm ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Highly Active Antiretroviral Therapy ◽  
Lymphoid Tissue ◽  
Jejunal Biopsy ◽  
Highly Active ◽  
Complete Restoration ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Gut-associated lymphoid tissue (GALT) harbors the majority of T lymphocytes in the body and is an important target for human immunodeficiency virus type 1 (HIV-1). We analyzed longitudinal jejunal biopsy samples from HIV-1-infected patients, during both primary and chronic stages of HIV-1 infection, prior to and following the initiation of highly active antiretroviral therapy (HAART) to determine the onset of CD4+ T-cell depletion and the effect of HAART on the restoration of CD4+ T cells in GALT. Severe depletion of intestinal CD4+ T cells occurred during primary HIV-1 infection. Our results showed that the restoration of intestinal CD4+ T cells following HAART in chronically HIV-1-infected patients was substantially delayed and incomplete. In contrast, initiation of HAART during early stages of infection resulted in near-complete restoration of intestinal CD4+ T cells, despite the delay in comparison to peripheral blood CD4+ T-cell recovery. DNA microarray analysis of gene expression profiles and flow-cytometric analysis of lymphocyte homing and cell proliferation markers demonstrated that cell trafficking to GALT and not local proliferation contributed to CD4+ T-cell restoration. Evaluation of jejunal biopsy samples from long-term HIV-1-infected nonprogressors showed maintenance of normal CD4+ T-cell levels in both GALT and peripheral blood. Our results demonstrate that near-complete restoration of mucosal immune system can be achieved by initiating HAART early in HIV-1 infection. Monitoring of the restoration and/or maintenance of CD4+ T cells in GALT provides a more accurate assessment of the efficacy of antiviral host immune responses as well as HAART.

scholarly journals Naïve T-Cell Dynamics in Human Immunodeficiency Virus Type 1 Infection: Effects of Highly Active Antiretroviral Therapy Provide Insights into the Mechanisms of Naïve T-Cell Depletion

2006 ◽  
Vol 80 (6) ◽  
pp. 2665-2674 ◽  
Author(s):  
Michele Di Mascio ◽  
Irini Sereti ◽  
Lynn T. Matthews ◽  
Ven Natarajan ◽  
Joseph Adelsberger ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Highly Active Antiretroviral Therapy ◽  
Cell Numbers ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Relative Change ◽  
Hiv 1

ABSTRACT Both naïve CD4+ and naïve CD8+ T cells are depleted in individuals with human immunodeficiency virus type 1 (HIV-1) infection by unknown mechanisms. Analysis of their dynamics prior to and after highly active antiretroviral therapy (HAART) could reveal possible mechanisms of depletion. Twenty patients were evaluated with immunophenotyping, intracellular Ki67 staining, T-cell receptor excision circle (TREC) quantitation in sorted CD4 and CD8 cells, and thymic computed tomography scans prior to and ∼6 and ∼18 months after initiation of HAART. Naïve T-cell proliferation decreased significantly during the first 6 months of therapy (P < 0.01) followed by a slower decline. Thymic indices did not change significantly over time. At baseline, naïve CD4+ T-cell numbers were lower than naive CD8+ T-cell numbers; after HAART, a greater increase in naïve CD4+ T cells than naïve CD8+ T cells was observed. A greater relative change (n-fold) in the number of TREC+ T cells/μl than in naïve T-cell counts was observed at 6 months for both CD4+ (median relative change [n-fold] of 2.2 and 1.7, respectively; P < 0.01) and CD8+ T cell pools (1.4 and 1.2; P < 0.01). A more pronounced decrease in the proliferation than the disappearance rate of naïve T cells after HAART was observed in a second group of six HIV-1-infected patients studied by in vivo pulse labeling with bromodeoxyuridine. These observations are consistent with a mathematical model where the HIV-1-induced increase in proliferation of naïve T cells is mostly explained by a faster recruitment into memory cells.

scholarly journals Evidence for Human Immunodeficiency Virus Type 1 Replication In Vivo in CD14+ Monocytes and Its Potential Role as a Source of Virus in Patients on Highly Active Antiretroviral Therapy

2002 ◽  
Vol 76 (2) ◽  
pp. 707-716 ◽  
Author(s):  
Tuofu Zhu ◽  
David Muthui ◽  
Sarah Holte ◽  
David Nickle ◽  
Feng Feng ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Antiretroviral Therapy ◽  
Human Immunodeficiency Virus Type ◽  
Highly Active Antiretroviral Therapy ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT In vitro studies show that human immunodeficiency virus type 1 (HIV-1) does not replicate in freshly isolated monocytes unless monocytes differentiate to monocyte-derived macrophages. Similarly, HIV-1 may replicate in macrophages in vivo, whereas it is unclear whether blood monocytes are permissive to productive infection with HIV-1. We investigated HIV-1 replication in CD14+ monocytes and resting and activated CD4+ T cells by measuring the levels of cell-associated viral DNA and mRNA and the genetic evolution of HIV-1 in seven acutely infected patients whose plasma viremia had been <100 copies/ml for 803 to 1,544 days during highly active antiretroviral therapy (HAART). HIV-1 DNA was detected in CD14+ monocytes as well as in activated and resting CD4+ T cells throughout the course of study. While significant variation in the decay slopes of HIV-1 DNA was seen among individual patients, viral decay in CD14+ monocytes was on average slower than that in activated and resting CD4+ T cells. Measurements of HIV-1 sequence evolution and the concentrations of unspliced and multiply spliced mRNA provided evidence of ongoing HIV-1 replication, more pronounced in CD14+ monocytes than in resting CD4+ T cells. Phylogenetic analyses of HIV-1 sequences indicated that after prolonged HAART, viral populations related or identical to those found only in CD14+ monocytes were seen in plasma from three of the seven patients. In the other four patients, HIV-1 sequences in plasma and the three cell populations were identical. CD14+ monocytes appear to be one of the potential in vivo sources of HIV-1 in patients receiving HAART.

scholarly journals Tenofovir-Based Highly Active Antiretroviral Therapy Is Associated with Superior CD4 T Cells Repopulation Compared to Zidovudine-Based HAART in HIV 1 Infected Adults

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Vitus Sambo Badii ◽  
Kwame Ohene Buabeng ◽  
Thomas Agyarko Poku ◽  
Arnold Donkor Forkuo ◽  
Bright Boafo Boamah ◽  
...  
Keyword(s):  
T Cells ◽  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Cd4 T Cells ◽  
Scientific Data ◽  
Highly Active ◽  
Median Period ◽  
Hiv 1 ◽  
Count Change ◽  
Zidovudine Regimen

Tenofovir-based highly active antiretroviral therapy (HAART) is one of the preferred first-line therapies in the management of HIV 1 infection. Ghana has since 2014 adopted this recommendation; however there is paucity of scientific data that reflects the safety and efficacy of the tenofovir-based therapy compared to zidovudine in the Ghanaian health system. This study sought to assess the comparative immune reconstitution potential between tenofovir and zidovudine-based HAART regimens, which includes lamivudine and efavirenz in combination therapy. It also aimed to investigate the adverse drug reactions/events (ADREs) associated with pharmacotherapy with these agents in a total of 106 HAART naïve HIV patients. The study included 80 patients in the tenofovir cohort while 26 patients were on the zidovudine regimen. The occurrence of HIV comorbidities profile was assessed at diagnosis and throughout the study period. The baseline CD4 T cells count of the participants was also assessed at diagnosis and repeated at a median period of five months (range 4–6 months), after commencing treatment with either tenofovir- or zidovudine-based HAART. After five months of the HAART, the tenofovir cohort recorded higher CD4 T cell count change from baseline compared to the zidovudine cohort (p<0.0001). The patients on the tenofovir-based HAART and female sex however appeared to be associated with more multiple ADREs.

scholarly journals Thiostrepton Reactivates Latent HIV-1 through the p-TEFb and NF-κB Pathways Mediated by Heat Shock Response

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Wen Peng ◽  
Zhongsi Hong ◽  
Xi Chen ◽  
Hongbo Gao ◽  
Zhuanglin Dai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Heat Shock ◽  
Viral Reactivation ◽  
Immune Recognition ◽  
Bryostatin 1 ◽  
Functional Cure ◽  
Cellular Models ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACT Antiretroviral therapy (ART) suppresses HIV-1 replication but fails to cure the infection. The presence of an extremely stable viral latent reservoir, primarily in resting memory CD4+ T cells, remains a major obstacle to viral eradication. The “shock and kill” strategy targets these latently infected cells and boosts immune recognition and clearance, and thus, it is a promising approach for an HIV-1 functional cure. Although some latency-reversing agents (LRAs) have been reported, no apparent clinical progress has been made, so it is still vital to seek novel and effective LRAs. Here, we report that thiostrepton (TSR), a proteasome inhibitor, reactivates latent HIV-1 effectively in cellular models and in primary CD4+ T cells from ART-suppressed individuals ex vivo. TSR does not induce global T cell activation, severe cytotoxicity, or CD8+ T cell dysfunction, making it a prospective LRA candidate. We also observed a significant synergistic effect of reactivation when TSR was combined with JQ1, prostratin, or bryostatin-1. Interestingly, six TSR analogues also show reactivation abilities that are similar to or more effective than that of TSR. We further verified that TSR upregulated expression of heat shock proteins (HSPs) in CD4+ T cells, which subsequently activated positive transcriptional elongation factor b (p-TEFb) and NF-κB signals, leading to viral reactivation. In summary, we identify TSR as a novel LRA which could have important significance for applications to an HIV-1 functional cure in the future.

scholarly journals Clinical Outcomes Improve with Highly Active Antiretroviral Therapy in Vertically HIV Type‐1–Infected Children

2006 ◽  
Vol 43 (2) ◽  
pp. 243-252 ◽  
Author(s):  
Salvador Resino ◽  
Rosa Resino ◽  
Jose Ma Bellon ◽  
Dariela Micheloud ◽  
Ma Dolores Gurbindo Gutierrez ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Clinical Outcomes ◽  
Highly Active Antiretroviral Therapy ◽  
Highly Active ◽  
Hiv Type 1
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