Human Immunodeficiency Virus Expression Research Articles

Mitotic deacetylase complex (MiDAC) recognizes the HIV-1 core promoter to control activated viral gene expression.

The human immunodeficiency virus (HIV) integrates into the host genome forming latent cellular reservoirs that are an obstacle for cure or remission strategies. Viral transcription is the first step in the control of latency and depends upon the hijacking of the host cell RNA polymerase II (Pol II) machinery by the 5' HIV LTR. Consequently, "block and lock" or "shock and kill" strategies for an HIV cure depend upon a full understanding of HIV transcriptional control. The HIV trans-activating protein, Tat, controls HIV latency as part of a positive feed-forward loop that strongly activates HIV transcription. The recognition of the TATA box and adjacent sequences of HIV essential for Tat trans-activation (TASHET) of the core promoter by host cell pre-initiation complexes of HIV (PICH) has been shown to be necessary for Tat trans-activation, yet the protein composition of PICH has remained obscure. Here, DNA-affinity chromatography was employed to identify the mitotic deacetylase complex (MiDAC) as selectively recognizing TASHET. Using biophysical techniques, we show that the MiDAC subunit DNTTIP1 binds directly to TASHET, in part via its CTGC DNA motifs. Using co-immunoprecipitation assays, we show that DNTTIP1 interacts with MiDAC subunits MIDEAS and HDAC1/2. The Tat-interacting protein, NAT10, is also present in HIV-bound MiDAC. Gene silencing revealed a functional role for DNTTIP1, MIDEAS, and NAT10 in HIV expression in cellulo. Furthermore, point mutations in TASHET that prevent DNTTIP1 binding block the reactivation of HIV by latency reversing agents (LRA) that act via the P-TEFb/7SK axis. Our data reveal a key role for MiDAC subunits DNTTIP1, MIDEAS, as well as NAT10, in Tat-activated HIV transcription and latency. DNTTIP1, MIDEAS and NAT10 emerge as cell cycle-regulated host cell transcription factors that can control activated HIV gene expression, and as new drug targets for HIV cure strategies.

The nuclear pore protein NUP98 impedes LTR-driven basal gene expression of HIV-1, viral propagation, and infectivity.

Nucleoporins (NUPs) are cellular effectors of human immunodeficiency virus-1 (HIV-1) replication that support nucleocytoplasmic trafficking of viral components. However, these also non-canonically function as positive effectors, promoting proviral DNA integration into the host genome and viral gene transcription, or as negative effectors by associating with HIV-1 restriction factors, such as MX2, inhibiting the replication of HIV-1. Here, we investigated the regulatory role of NUP98 on HIV-1 as we observed a lowering of its endogenous levels upon HIV-1 infection in CD4+ T cells. Using complementary experiments in NUP98 overexpression and knockdown backgrounds, we deciphered that NUP98 negatively affected HIV-1 long terminal repeat (LTR) promoter activity and lowered released virus levels. The negative effect on promoter activity was independent of HIV-1 Tat, suggesting that NUP98 prevents the basal viral gene expression. ChIP-qPCR showed NUP98 to be associated with HIV-1 LTR, with the negative regulatory element (NRE) of HIV-1 LTR playing a dominant role in NUP98-mediated lowering of viral gene transcription. Truncated mutants of NUP98 showed that the attenuation of HIV-1 LTR-driven transcription is primarily contributed by its N-terminal region. Interestingly, the virus generated from the producer cells transiently expressing NUP98 showed lower infectivity, while the virus generated from NUP98 knockdown CD4+ T cells showed higher infectivity as assayed in TZM-bl cells, corroborating the anti-HIV-1 properties of NUP98. Collectively, we show a new non-canonical function of a nucleoporin adding to the list of moonlighting host factors regulating viral infections. Downregulation of NUP98 in a host cell upon HIV-1 infection supports the concept of evolutionary conflicts between viruses and host antiviral factors.

Anti-inflammatory effects of CBD in human microglial cell line infected with HIV-1

Human immunodeficiency virus (HIV) infection is associated with a chronic inflammatory stage and continuous activation of inflammasome pathway. We studied the anti-inflammatory effects of the compound cannabidiol (CBD) in comparison with Δ (9)-tetrahydrocannabinol [Δ(9)-THC] in human microglial cells (HC69.5) infected with HIV. Our results showed that CBD reduced the production of various inflammatory cytokines and chemokines such as MIF, SERPIN E1, IL-6, IL-8, GM-CSF, MCP-1, CXCL1, CXCL10, and IL-1 β compared to Δ(9)-THC treatment. In addition, CBD led to the deactivation of caspase 1, reduced NLRP3 gene expression which play a crucial role in the inflammasome cascade. Furthermore, CBD significantly reduced the expression of HIV. Our study demonstrated that CBD has anti-inflammatory properties and exhibits significant therapeutic potential against HIV-1 infections and neuroinflammation.

Klotho Expression in Aging and Disease

Klotho is a regulatory anti‐aging protein that is significantly expressed in the choroid plexus, plays an important role in regulating the immune response in the CNS, and diminishes with age. It is known that a decline of klotho expression has been linked to significant neuroinflammation, oxidative damage in the neural parenchyma, and decline in neurocognitive functions. As the choroid plexus is a known reservoir for latent Human Immunodeficiency Virus (HIV) infection, the relationship between HIV and klotho expression could be a cause of the neurocognitive dysfunction that accompanies HIV infections. The objective of this project was to observe levels of klotho expression in the choroid plexus in a Simian Immunodeficiency Virus (SIV) model of HIV infection, as well as to determine a pattern of age‐related decline in klotho expression. To carry out the study, Choroid plexus samples of Rhesus macaques of various ages and SIV‐infection status were studied. The tissues were stained using immunohistochemistry for polyclonal klotho, structural proteins (vimentin), and nuclei (DAPI), and imaged at varying magnifications of 4x, 10x, and 40x. The images obtained were then analyzed using the fluorescent imaging software Fiji. The epithelial cells of the choroid plexus were measured for their fluorescence intensity to measure their relative klotho expression levels. Although klotho expression was varied in the uninfected Rhesus macaques, there was an overall decreasing trend with the advancement of age. In SIV‐infected Rhesus macaques, the choroid plexus had significantly less klotho expression than the uninfected control group regardless of age (p=0.01). Analysis of the uninfected data shows that there was a decreasing pattern of klotho expression in Rhesus macaques. The variability of klotho levels in the uninfected individuals can be attributed to genetic variations between individuals. However, SIV infection significantly reduced klotho expression in the choroid plexus in comparison to uninfected individuals. This decrease in klotho expression was regardless of age. The exact mechanism in which SIV diminishes klotho expression is unknown and additional studies are warranted to examine this phenomenon.

Impact of Tamoxifen on Vorinostat-Induced Human Immunodeficiency Virus Expression in Women on Antiretroviral Therapy: AIDS Clinical Trials Group A5366, The MOXIE Trial.

Biological sex and the estrogen receptor alpha (ESR1) modulate human immunodeficiency virus (HIV) activity. Few women have enrolled in clinical trials of latency reversal agents (LRAs); their effectiveness in women is unknown. We hypothesized that ESR1 antagonism would augment induction of HIV expression by the LRA vorinostat. AIDS Clinical Trials Group A5366 enrolled 31 virologically suppressed, postmenopausal women on antiretroviral therapy. Participants were randomized 2:1 to receive tamoxifen (arm A, TAMOX/VOR) or observation (arm B, VOR) for 5 weeks followed by 2 doses of vorinostat. Primary end points were safety and the difference between arms in HIV RNA induction after vorinostat. Secondary analyses included histone 4 acetylation, HIV DNA, and plasma viremia by single copy assay (SCA). No significant adverse events were attributed to study treatments. Tamoxifen did not enhance vorinostat-induced HIV transcription (between-arm ratio, 0.8; 95% confidence interval [CI], .2-2.4). Vorinostat-induced HIV transcription was higher in participants with increases in H4Ac (fold increase, 2.78; 95% CI, 1.34-5.79) vs those 9 who did not (fold increase, 1.04; 95% CI, .25-4.29). HIV DNA and SCA plasma viremia did not substantially change. Tamoxifen did not augment vorinostat-induced HIV RNA expression in postmenopausal women. The modest latency reversal activity of vorinostat, postmenopausal status, and low level of HIV RNA expression near the limits of quantification limited assessment of the impact of tamoxifen. This study is the first HIV cure trial done exclusively in women and establishes both the feasibility and necessity of investigating novel HIV cure strategies in women living with HIV. NCT03382834.

Central nervous system (CNS) transcriptomic correlates of human immunodeficiency virus (HIV) brain RNA load in HIV-infected individuals

To generate new mechanistic hypotheses on the pathogenesis and disease progression of neuroHIV and identify novel therapeutic targets to improve neuropsychological function in people with HIV, we investigated host genes and pathway dysregulations associated with brain HIV RNA load in gene expression profiles of the frontal cortex, basal ganglia, and white matter of HIV+ patients. Pathway analyses showed that host genes correlated with HIV expression in all three brain regions were predominantly related to inflammation, neurodegeneration, and bioenergetics. HIV RNA load directly correlated particularly with inflammation genesets representative of cytokine signaling, and this was more prominent in white matter and the basal ganglia. Increases in interferon signaling were correlated with high brain HIV RNA load in the basal ganglia and the white matter although not in the frontal cortex. Brain HIV RNA load was inversely correlated with genesets that are indicative of neuronal and synaptic genes, particularly in the cortex, indicative of synaptic injury and neurodegeneration. Brain HIV RNA load was inversely correlated with genesets that are representative of oxidative phosphorylation, electron transfer, and the tricarboxylic acid cycle in all three brain regions. Mitochondrial dysfunction has been implicated in the toxicity of some antiretrovirals, and these results indicate that mitochondrial dysfunction is also associated with productive HIV infection. Genes and pathways correlated with brain HIV RNA load suggest potential therapeutic targets to ameliorate neuropsychological functioning in people living with HIV.

Gag p24 Is a Marker of Human Immunodeficiency Virus Expression in Tissues and Correlates With Immune Response.

We demonstrate that human immunodeficiency virus (HIV) gag p24 protein is more readily detected in gut and lymph node tissues than in blood CD4+ T cells and correlates better with CD4 count during antiretroviral therapy (ART). Gut p24 levels also measurably decline with ART in natural controllers. During ART, gut p24 expression is more strongly associated both with HIV-specific CD8+ T-cell frequency and plasma soluble CD14 levels than gut HIV RNA expression. This study supports using gag p24 as a marker of HIV expression in HIV+ tissues to study effects of viral persistence and to monitor efficacy of treatment in HIV-based clearance studies.

HIV-induced cancer--all paths leading to Rome

BackgroundAlthough several viruses have been proved to induce host specific microRNAs (miRNAs, miRs), the expression of functional miRNAs induced by Human Immunodeficiency Virus 1 (HIV-1) infection is still unknown. The variation of the expression of HIV-1 inducing miRNAs both in vitro and in vivo (in all types of infected patient groups) implies that these specific miRNAs have potential roles in the development of diseases. However, few researches have noticed the roles of these serum miRNAs. In this study, we attempted to establish a macrocontrol regulation system and simulate the influence of HIV-1 inducing miRNAs during the development of cancer. MethodsThe miRbase, FunRich software, miRtarbase, STRING, TargetScanhuman, Cytoscape plugin ClueGO/Cluepedia/STRING, DAVID Bioinformatics Resources and GEO database were comprehensively employed in this bioinformatics study. ResultsThe miRNAs in the serum of AIDS patients and its target genes have different expression levels in serum, an array of which are associated with cancer and metabolism signaling pathways. Moreover, the emerging role of miRNAs in HIV-1 infection is also involved in human cancer, using TCGA data integrative analysis. ConclusionsTherefore, we infer that serum miRNAs in HIV-1 infection may play important roles in HIV-induced cancer and could be used as a potential biomarker for HIV-cancers detection.

Total Synthesis of (±)-Prostratin

Summary Prostratin, a highly complex diterpene natural product, is a pre-clinical candidate in developing a cure for HIV-1 infection and also a potent and selective inhibitor of several tumors. Despite nearly 40 years of progress, prostratin and related natural products still present formidable challenges for synthetic chemists. Here, we report a total synthesis of (±)-prostratin that proceeds in 23 steps from cyclopentadiene. The synthetic strategy includes rapid assembly of the tricyclic core and highly controlled establishment of the densely functionalized C ring, featuring an array of stereoselective transformations including alkoxide-guided 1,4-additions and cyclopropane formation. This work should enable further explorations of chemical and biological spaces based on prostratin and related natural products.

Histone deacetylase inhibitor chidamide promotes reactivation of latent human immunodeficiency virus by introducing histone acetylation

Highly active antiretroviral therapy can reduce the human immunodeficiency virus (HIV) viral load in the plasma to undetectable levels. However, because of the presence of latent HIV reservoirs, it is difficult to completely eradicate HIV in infected patients. Our objective was to assess the potency of chidamide, a novel histone deacetylase inhibitor recently approved for cancer treatment by the China Food and Drug Administration, to reactivate latent HIV-1 via histone acetylation. Viral reactivities of chidamide were accessed in 2 latent HIV pseudotype virus cell reporter systems (J-Lat Tat-green fluorescent protein clone A72 and TZM-bl), a latently infected full-length HIV virus cell system (U1/HIV), and resting CD4+ T cells from 9 HIV-infected patients under highly active antiretroviral therapy with undetectable viral load. Chidamide was able to increase HIV expression in each cell line, as evidenced by green fluorescent protein, luciferase activity, and p24, as well as to reactivate latent HIV-1 in primary CD4+ T cells of HIV-infected patients. Histone acetylation adjacent to the HIV promoter in A72 cells was determined by chromatin immunoprecipitation. Chidamide was able to increase histone H3 and H4 acetylation at the HIV promoter. In brief, chidamide induced the reactivation of latent HIV in pseudotype virus reporter cells, latently infected cells, and primary CD4+ T cells, making this compound an attractive option for future clinical trials.

D-106 Chromatin Functional States Correlate with the Reversal of Latently HIV-1 Infected Primary CD4+ T cells

Current antiretroviral therapies (ART) do not allow for the eradication of the human immunodeficiency virus (HIV) due to the presence of latent proviruses in rare, long-lived resting CD4+ T cells. The main research efforts to eliminate the viral reservoir are focused on the use of latency reversing agents (LRAs) to force the reactivation of the latent provirus, while maintaining ART to prevent de novo infections. Subsequently, reactivation of HIV expression would kill reservoir cells via viral cytopathic effects and/or immune clearance (“shock and kill” strategy). So far, no LRAs tested in clinical trials have succeeded in reducing the reservoir. Furthermore, there is limited understanding as to why some latent proviruses are being induced, while others are not. We used an improved dual-fluorescent HIV reporter (GKO), which distinguishes productively infected cells from the latent population, to investigate the efficacy of the “shock and kill” strategy. In addition, GKO provides a unique opportunity to (1) explore the impact of HIV integration site specificity on the fate of the infection, and to (2) characterize the inducible subpopulation of latently infected cells, since it allows the isolation of inducible latent and non-inducible latent populations from the productively infected majority. We first showed that our patients' data was consistent with previously published studies. However, we found that at most 5% of GKO latent proviruses were reactivated. Moreover, the analysis of HIV-1 integration sites from productively, non-inducible and inducible latently infected populations reveals heterogeneity within the latent infections. In contrast to non-inducible latent infections, the integration sites of inducible latent proviruses have similar features to those of productive proviruses, thus demonstrating a prominent role for the site of integration and its chromatin context for the fate of the initial infection as well as for latency reversal. Our study shows an important roadblock for the “shock and kill” approach to reservoir eradication. Differences between inducible and permanently latent reservoir cells suggest that complete reservoir reactivation and eradication with LRAs may prove impossible, and that a multipronged “functional cure” approach may be necessary.

The interferon-induced protein kinase R: the base of a riboprotein scaffolding regulating the human immunodeficiency virus.

The interferon-induced RNA-activated Protein Kinase (PKR) targets the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2α) whose phosphorylation blocks translation initiation of cellular and viral mRNAs. PKR is activated at the beginning of human immunodeficiency virus (HIV) infection by low levels of the HIV Transactivation Response (TAR) RNA and by the cellular PKR Activator (PACT), which contributes to a reduced viral replication. During HIV replication, the viral Tat protein and high production of TAR RNA decrease PKR activation. The cellular TAR RNA Binding Protein (TRBP) and Adenosine Deaminase Acting on RNA (ADAR1) also prevent PKR activation, while HIV expression changes PACT function to become a PKR inhibitor. Therefore, HIV recruits viral and cellular factors to counteract PKR antiviral activity. In addition, PKR antiviral function was positively selected during evolution due to contacts with viral factors inhibiting its function. The riboprotein scaffolding such as the one that inhibits PKR during HIV replication may exist for other antiviral factors.

The interferon-induced protein kinase R: the base of a riboprotein scaffolding regulating the human immunodeficiency virus.

The interferon-induced RNA-activated Protein Kinase (PKR) targets the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2α) whose phosphorylation blocks translation initiation of cellular and viral mRNAs. PKR is activated at the beginning of human immunodeficiency virus (HIV) infection by low levels of the HIV Transactivation Response (TAR) RNA and by the cellular PKR Activator (PACT), which contributes to a reduced viral replication. During HIV replication, the viral Tat protein and high production of TAR RNA decrease PKR activation. The cellular TAR RNA Binding Protein (TRBP) and Adenosine Deaminase Acting on RNA (ADAR1) also prevent PKR activation, while HIV expression changes PACT function to become a PKR inhibitor. Therefore, HIV recruits viral and cellular factors to counteract PKR antiviral activity. In addition, PKR antiviral function was positively selected during evolution due to contacts with viral factors inhibiting its function. The riboprotein scaffolding such as the one that inhibits PKR during HIV replication may exist for other antiviral factors.

HIV Antibody Level as a Marker of HIV Persistence and Low-Level Viral Replication.

Human immunodeficiency virus (HIV) antibodies are generated and maintained by ongoing systemic expression of HIV antigen. We investigated whether HIV antibody responses as measured by high-throughput quantitative and qualitative assays could be used to indirectly measure persistent HIV replication in individuals receiving antiretroviral therapy (ART). HIV antibody responses were measured over time in the presence or absence of suppressive ART and were compared to the HIV reservoir size and expression of antiviral restriction factors. Among untreated individuals, including both elite controllers (ie, persons with a viral load of ≤40 copies/mL) and noncontrollers, antibody parameters were stable over time and correlated with the individual viral load. Viral suppression with ART led to a progressive decline in antibody responses after treatment induction that persisted for 5-7 years. Higher levels of HIV antibodies during suppressive therapy were associated with later initiation of ART after infection, with higher DNA and cell-associated RNA levels, and with lower expression of multiple anti-HIV host restriction factors. These findings suggest that declining antibody levels during ART reflect lower levels of antigen production and/or viral replication in the persistent HIV reservoir. Results of relatively inexpensive and quantitative HIV antibody assays may be useful indirect markers that enable efficient monitoring of the viral reservoir and suppression during functional-cure interventions.

HIV Exploits Antiviral Host Innate GCN2-ATF4 Signaling for Establishing Viral Replication Early in Infection.

ABSTRACTAntiviral innate host defenses against acute viral infections include suppression of host protein synthesis to restrict viral protein production. Less is known about mechanisms by which viral pathogens subvert host antiviral innate responses for establishing their replication and dissemination. We investigated early innate defense against human immunodeficiency virus (HIV) infection and viral evasion by utilizing human CD4+ T cell cultures in vitro and a simian immunodeficiency virus (SIV) model of AIDS in vivo. Our data showed that early host innate defense against the viral infection involves GCN2-ATF4 signaling-mediated suppression of global protein synthesis, which is exploited by the virus for supporting its own replication during early viral infection and dissemination in the gut mucosa. Suppression of protein synthesis and induction of protein kinase GCN2-ATF4 signaling were detected in the gut during acute SIV infection. These changes diminished during chronic viral infection. HIV replication induced by serum deprivation in CD4+ T cells was linked to the induction of ATF4 that was recruited to the HIV long terminal repeat (LTR) to promote viral transcription. Experimental inhibition of GCN2-ATF4 signaling either by a specific inhibitor or by amino acid supplementation suppressed the induction of HIV expression. Enhancing ATF4 expression through selenium administration resulted in reactivation of latent HIV in vitro as well as ex vivo in the primary CD4+ T cells isolated from patients receiving suppressive antiretroviral therapy (ART). In summary, HIV/SIV exploits the early host antiviral response through GCN2-ATF4 signaling by utilizing ATF4 for activating the viral LTR transcription to establish initial viral replication and is a potential target for HIV prevention and therapy.

586. Dimerization Inhibition of HIV-1 RNA by 2’-Deoxy-2’-fluoro-beta-D-arabinose Nucleic Acid (2’-FANA) Modified Antisense Oligonucleotides Results in Potential Inhibition of Viral Expression

Human immunodeficiency virus-1 (HIV-1) viral particle contains two copies of genomic RNA, which is known to form dimers via intermolecular interactions. The dimerization process is initiated by the formation of a kissing-loop dimer through base pairing of the palindromic loop sequence within dimerization initiation site (DIS). It has been shown that mutation or inhibitions of the DIS severely affect the viral infectivity. Antisense oligonucleotides (AONs) are single-stranded synthetic oligonucleotides that recognize target RNAs via Watson-Crick base pairing and cause post-translational inhibition. The mechanisms are believed to be RNase H cleavage of target RNA, steric hindrance of the translation machinery or prevention of RNA-RNA or RNA-protein interactions. While AONs offer promising solutions for variety of human diseases in preclinical studies and many of these are currently in clinical studies, a number of challenges still hamper their translation from the bench to the bedside, the most significant of which include target accessibility, off target effects, poor extracellular and intracellular stability and effective delivery into target cells. 2’-deoxy-2’-fluoro-beta-D-arabinose nucleic acid (2’-FANA) modification significantly enhances chemical and intracellular stability, as well as binding to the target RNA, forming stable heteroduplex structures. Moreover, 2’-FANA modification has been shown to facilitate gymnotic cellular delivery, a carrier-free method of achieving cellular uptake. Thus, we hypothesized that 2’-FANA modified AONs that bind HIV-1 DIS can inhibit dimerization, and subsequently inhibit viral expression. Firstly, we tested gymnotic delivery of 2’-FANA modified AONs to peripheral blood mononuclear cells (PBMCs) freshly isolated from human blood. Cellular uptake of the 2’-FANA AONs without any transfection reagent were observed in live-cell confocal microscopy analysis as soon as an hour after adding AONs. Next, the HIV-1 inhibitory effect of the 2’-FANA AONs was tested in HIV-1 infected PBMCs. Cell supernatant was collected and HIV-1 expression was measured by HIV-1 p24 ELISA. The 2’-FANA AONs strongly inhibited HIV-1 expression as long as two weeks after 2’-FANA AONs treatment. A mechanism study showed that the 2’-FANAAONs work against HIV by steric blocking of dimerization. Unlike most oligonucleotide therapeutics, 2’-FANA AONs can be gymnotically delivered into PBMCs. This fact makes 2’-FANA AONs great drug candidates for antiretroviral therapy.

Editorial Commentary: Reversing Latency in HIV-Infected Patients

The inability of combination antiretroviral treatment (cART) to eradicate human immunodeficiency virus (HIV) infection has renewed scientific interest in curative strategies [1]. The primary barrier preventing eradication of HIV by cART is a pool of long-lived latently infected cells of which memory CD4 + T cells appear to be the most important. These latently infected cells harbor integrated proviral DNA capable of resuming HIV expression and fueling viral rebound upon cessation of cART. One strategy to deplete this viral reservoir has been termed “kick and kill,” indicating a 2-step process by which expression of the latent virus is reactivated by a latency-reversing agent followed by elimination of the infected cell by either cell apoptotic/cytolytic mechanism or by immune-mediated clearance. The hunt for pharmacological interventions capable of reactivating HIV from the resting state and hence deliver the first step of this strategy is now on. In the study by Spivak et al in this issue of Clinical Infectious Diseases, the antialcoholism drug disulfiram was tested in 15 virologically suppressed patients with HIV for its ability to reactivate latent HIV. Two questions were asked in this study: First, can disulfiram activate latent HIV as determined by increases in residual viremia? Second, can HIV reactivation with disulfiram lead to a reduction in the size of the latent reservoir? As for the first point, the jury is still out. Overall, during 14 days of disulfiram dosing, there was no significant effect on the level of residual viremia measured by the single-copy assay. Despite this, there are 2 findings supporting the latencyreversing capacity of disulfiram. In 10 patients with measurements 2 hours after the first dose, an increase in residual viremia was observed. Furthermore, during the postdosing phase of the study, an overall increase in viral particle production above baseline was noted. Another class of compounds, the histone deacetylase inhibitors (HDACi), has recently been found to reactivate HIV in CD4 T cells in vivo [2, 3] although these 2 studies investigating the potential of vorinostat to reactive HIV failed to detect any increases in plasma viremia. Unfortunately, the study by

Reactivation of Latent HIV-1 by Inhibition of BRD4

HIV-1 depends on many host factors for propagation. Other host factors, however, antagonize HIV-1 and may have profound effects on viral activation. Curing HIV-1 requires the reduction of latent viral reservoirs that remain in the face of antiretroviral therapy. Using orthologous genetic screens, we identified bromodomain containing 4 (BRD4) as a negative regulator of HIV-1 replication. Antagonism of BRD4, via RNA interference or with a small molecule inhibitor, JQ1, both increased proviral transcriptional elongation and alleviated HIV-1 latency in cell-line models. In multiple instances, JQ1, when used in combination with the NF-κB activators Prostratin or PHA, enhanced the invitro reactivation of latent HIV-1 in primary Tcells. These data are consistent with a model wherein BRD4 competes with the virus for HIV-1 dependency factors (HDFs) and suggests that combinatorial therapies that activate HDFs and antagonize HIV-1 competitive factors may be useful for curing HIV-1 infection.

British HIV Association guidelines for the management ofHIVinfection in pregnant women 2012

British HIV Association guidelines for the management of<scp>HIV</scp>infection in pregnant women 2012

Effect of Histone Deacetylase Inhibitors on HIV Production in Latently Infected, Resting CD4+ T Cells From Infected Individuals Receiving Effective Antiretroviral Therapy

Persistence of the latent viral reservoir has been recognized as a major obstacle to eradicating human immunodeficiency virus (HIV) in infected individuals receiving antiretroviral therapy. It has been suggested that histone deacetylase inhibitors (HDACis) may purge HIV in the latent viral reservoir. However, the effect of HDACis on the degree and extent of HIV expression in the latent viral reservoir has not been fully delineated. Here we demonstrate that HDACis do not induce HIV production in the latent viral reservoir of aviremic individuals. Therefore, alternative therapeutic strategies may be necessary to eliminate HIV in the latent viral reservoir.