HIV-1 expression within resting CD4+ T cells after multiple doses of vorinostat.

Background: A single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4(+) T cells of treated, aviremic human immunodeficiency virus (HIV)-positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge.

Methods: Five participants in whom resting CD4(+) T-cell-associated HIV RNA (rc-RNA) increased after a single dose of VOR agreed to receive daily VOR Monday through Wednesday for 8 weekly cycles.

Generation of HIV latency in humanized BLT mice.

Here we demonstrate that a combination of tenofovir, emtricitabine, and raltegravir effectively suppresses peripheral and systemic HIV replication in humanized BLT mice. We also demonstrate that antiretroviral therapy (ART)-treated humanized BLT mice harbor latently infected resting human CD4+ T cells that can be induced ex vivo to produce HIV. We observed that the levels of infected resting human CD4+ T cells present in BLT mice are within the range of those observed circulating in patients undergoing suppressive ART.

Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells.

Objectives: Valproic acid and intensified antiretroviral therapy may deplete resting CD4+ T-cell HIV infection. We tested the ability of valproic acid to deplete resting CD4+ T-cell infection in patients receiving standard antiretroviral therapy.

Methods: Resting CD4+ T-cell infection was measured in 11 stably aviremic volunteers twice prior to, and twice after Depakote ER 1000 mg was added to standard antiretroviral therapy.

Hexamethylbisacetamide and disruption of human immunodeficiency virus type 1 latency in CD4(+) T cells.

Background: Novel therapeutic approaches are needed to attack persistent proviral human immunodeficiency type 1 (HIV-1) infection. Hexamethylbisacetamide (HMBA), a hybrid bipolar compound, induces expression of the HIV-1 promoter in the long terminal repeat (LTR) region in a Tat-independent manner but mimics the effect of Tat, overcoming barriers to LTR expression and increasing the processivity of LTR transcription complexes.

Methods: We studied alterations in cellular factors and their LTR occupancy induced by HMBA in models of latent HIV-1 infection.

Attacking HIV provirus: therapeutic strategies to disrupt persistent infection.

The therapeutic armamentarium for human immunodeficiency virus type 1 (HIV-1) infection continues to expand. New targets such as entry and integration have recently been successfully exploited. However, HIV-infected patients in need of treatment are currently committed to lifelong suppressive therapy.

Attacking latent HIV provirus: from mechanism to therapeutic strategies.

Purpose Of Review: The persistence of small population integrated proviral HIV genomes capable of expressing HIV within long-lived CD4 T cells is a fundamental obstacle to the eradication or cure of HIV infection. As potent antiretroviral therapy by itself appears to be an impractical approach to the eradication of this quiescent reservoir of HIV infection, new approaches are required.

Recent Findings: Initial studies failed to demonstrate that simultaneous, intensive antiretroviral therapy in combination with global inducers of CD4 T-cell activation could eradicate HIV infection.

Delayed spread and reduction in virus titer after anterior chamber inoculation of a recombinant of HSV-1 expressing IL-16.

Purpose: The timing of T-cell infiltration of the hypothalamus is crucial in the prevention of bilateral retinitis in mice inoculated with HSV-1 through the anterior chamber (AC). In H129-infected mice, T-cells are recruited to the suprachiasmatic nuclei of the hypothalamus too late to protect infected mice from development of bilateral retinitis. The purpose of these studies was to determine whether alteration of T-cell recruitment to the hypothalamus would affect the timing and pattern of virus spread after AC inoculation.

Infiltration of T-lymphocytes in the brain after anterior chamber inoculation of a neurovirulent and neuroinvasive strain of HSV-1.

Following anterior chamber (AC) inoculation of BALB/c mice with the KOS strain of herpes simplex virus type 1 (HSV-1), or with H129, a neuroinvasive and neurovirulent strain of HSV-1, both strains of virus spread from the injected eye through the brain to cause retinitis. However, KOS-infected mice develop retinitis in the uninoculated eye only, whereas H129-infected mice develop bilateral retinitis. Previous studies have shown that infiltrating T-cells in the suprachiasmatic nuclei (SCN) of the hypothalamus of KOS-infected mice concomitant with or before virus protect KOS-infected mice from ipsilateral retinitis.

Rapid spread of a neurovirulent strain of HSV-1 through the CNS of BALB/c mice following anterior chamber inoculation.

Following uniocular anterior chamber (AC) inoculation of BALB/c mice with the KOS strain of herpes simplex virus type 1 (HSV-1), virus spreads from the injected eye to the ipsilateral suprachiasmatic nucleus (SCN) in the central nervous system (CNS) to infect the optic nerve and retina of the contralateral eye, and mice develop retinitis in that eye only. In contrast, after AC inoculation of BALB/c mice with the H129 strain of HSV-1, mice develop bilateral retinitis. The pathway(s) by which H129 spreads to cause bilateral retinitis is not known.