Histone deacetylase inhibitor Scriptaid reactivates latent HIV-1 promoter by inducing histone modification in in vitro latency cell lines.

Human immunodeficiency virus type 1 (HIV-1) latency remains a major problem for the eradication of viruses in infected individuals undergoing highly active anti-retroviral therapy. By inhibiting HIV-1 gene expression and virus production, histone deacetylase (HDAC) may contribute to the quiescence of HIV-1 within resting CD4+ T cells. A novel HDAC inhibitor, Scriptaid, has been found to have robust activity and lower toxicity compared to trichostatin A (TSA).

Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation.

The development of highly active antiretroviral therapy (HAART) to treat individuals infected with HIV-1 has dramatically improved patient outcomes, but HAART still fails to cure the infection. The latent viral reservoir in resting CD4+ T cells is a major barrier to virus eradication. Elimination of this reservoir requires reactivation of the latent virus.

Role of natural killer cells in a cohort of elite suppressors: low frequency of the protective KIR3DS1 allele and limited inhibition of human immunodeficiency virus type 1 replication in vitro.

Natural killer (NK) cells are associated with the innate immune response and are important in many viral infections. Recent studies indicate that NK cells can control human immunodeficiency virus type 1 (HIV-1) replication. We studied the effect of NK cells on HIV-1 replication in a subpopulation of HIV-1-infected individuals termed elite suppressors (ES) or elite controllers.

Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough.

Integrated HIV-1 genomes are found within actively transcribed host genes in latently infected CD4(+) T cells. Readthrough transcription of the host gene might therefore suppress HIV-1 gene expression and promote the latent infection that allows viral persistence in patients on therapy. To address the effect of host gene readthrough, we used homologous recombination to insert HIV-1 genomes in either orientation into an identical position within an intron of an actively transcribed host gene, hypoxanthine-guanine phosphoribosyltransferase (HPRT).

Transmission of human immunodeficiency virus type 1 from a patient who developed AIDS to an elite suppressor.

Elite suppressors (ES) are untreated human immunodeficiency virus type 1 (HIV-1)-infected patients who maintain viral loads of <50 copies/ml. The mechanisms involved in this control of viral replication remain unclear. Prior studies suggested that these patients, as well as long-term nonprogressors, are infected with defective HIV-1 variants.

The role of protective HCP5 and HLA-C associated polymorphisms in the control of HIV-1 replication in a subset of elite suppressors.

Elite suppressors (ES) are untreated HIV-1-infected patients who maintain undetectable viral loads. A recent whole-genome analysis identified two independent polymorphisms associated with low viral loads in untreated HIV-1 infection. We screened 16 ES; none were positive for the protective HLA complex 5 gene polymorphism, and only four were positive for the protective polymorphism associated with the HLA-C gene.

Experimental approaches to the study of HIV-1 latency.

Viral latency is a reversibly non-productive state of infection that allows some viruses to evade host immune responses. As a consequence of its tropism for activated CD4(+) T cells, HIV-1 can establish latent infection in resting memory CD4(+) T cells, which are generated when activated CD4(+) T cells return to a quiescent state. Latent HIV-1 persists as a stably integrated but transcriptionally silent provirus.

S-nitrosylation of N-ethylmaleimide sensitive factor mediates surface expression of AMPA receptors.

Postsynaptic AMPA receptor (AMPAR) trafficking mediates some forms of synaptic plasticity that are modulated by NMDA receptor (NMDAR) activation and N-ethylmaleimide sensitive factor (NSF). We report that NSF is physiologically S-nitrosylated by endogenous, neuronally derived nitric oxide (NO). S-nitrosylation of NSF augments its binding to the AMPAR GluR2 subunit.

Intermittent HIV-1 viremia (Blips) and drug resistance in patients receiving HAART.

Context: Many patients infected with human immunodeficiency virus type 1 (HIV-1) and receiving highly active antiretroviral therapy experience intermittent episodes of detectable viremia ("blips"), which may raise concerns about drug resistance, lead to costly repeat measurements of viral RNA, and sometimes trigger alterations in therapy.

Objective: To test the hypothesis that blips represent random biological and statistical variation around mean steady-state HIV-1 RNA levels slightly below 50 copies/mL rather than biologically significant elevations in viremia.

Design, Setting, And Patients: Between June 19, 2003, and February 9, 2004, patients receiving therapy underwent intensive sampling (every 2-3 days) over 3 to 4 months to define the frequency, magnitude, and duration of blips and their association with drug levels and other clinical variables.

G-->A hypermutation in protease and reverse transcriptase regions of human immunodeficiency virus type 1 residing in resting CD4+ T cells in vivo.

In vitro studies have shown that the host cytidine deaminase APOBEC3G causes lethal hypermutation in human immunodeficiency virus type 1 reverse transcripts unless its incorporation into virions is blocked by Vif. By examining stably archived sequences in resting CD4+ T cells, we show that hypermutation occurs in most if not all infected individuals. Hypermutated sequences comprised >9% of archived species in resting CD4+ T cells but were not found in plasma virus.

The multifactorial nature of HIV-1 latency.

HIV-1 can avoid host immune responses and antiretroviral drugs through the latent infection of resting memory CD4(+) T cells. Recently, latent viral genomes have been shown to reside within the introns of active host genes. Therefore, latency is not simply due to an inaccessibility of the integrated proviruses to the transcriptional machinery.

Resting CD4+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals carry integrated HIV-1 genomes within actively transcribed host genes.

Resting CD4+ T-cell populations from human immunodeficiency virus type 1 (HIV-1)-infected individuals include cells with integrated HIV-1 DNA. In individuals showing suppression of viremia during highly active antiretroviral therapy (HAART), resting CD4+ T-cell populations do not produce virus without cellular activation. To determine whether the nonproductive nature of the infection in resting CD4+ T cells is due to retroviral integration into chromosomal regions that are repressive for transcription, we used inverse PCR to characterize the HIV-1 integration sites in vivo in resting CD4+ T cells from patients on HAART.

Male fertility is compatible with an Arg(840)Cys substitution in the AR in a large Chinese family affected with divergent phenotypes of AR insensitivity syndrome.

Androgen insensitivity syndrome (AIS) is a disorder of male sexual development caused by an absent or dysfunctional AR. Fertile cases with mild AIS and slightly impaired AR activity had been reported in literature, and their external genitalia were documented to be usually normal or subnormal. We reported here an Arg(840)Cys substitution in the AR gene in a large Chinese pedigree affected with AIS.