Therapy for persistent HIV

Abstract

Given the scope of the human immunodeficiency virus (HIV) pandemic, millions of people will need of chronic antiretroviral therapy (ART) for decades into the future. It is hoped that progress in prevention of HIV infection can be made, but there have been few successes in this effort thus far. ART also presents formidable problems. Therefore, research must continue on improvements in prevention and treatment, but future HIV research should now also seek to develop temporally contained therapies capable of eradicating HIV infection. This review will explore what is known about the mechanisms that restrain HIV expression and result in persistent, latent proviral infection, and what these mechanisms tell us about potential approaches towards eradication of HIV infection.

Figure 1. Decay of plasma viremia induced by current antiretroviral therapy (ART)

Initiation of potent ART results in a precipitous decline in measurable plasma viremia. Level of viremia drop below the level of detection of commonly available clinical assays (ca. 50 copies of HIV-1 RNA/ml) within weeks, but sometimes take up to 6 months to decline below the limit of detection. This initial phase of decay often occurs in a biphasic pattern, as illustrated here, but a monophasic decline can be seen with regimens that contain an integrase inhibitor. After this initial decline, the slope(s) of further declines in levels of plasma viremia appear to gradually approach zero. Stable production of low levels of viremia are detectable in a minority of patients with more sensitive research assays (a), and even lower levels may be established in most patient at levels that cannot even be detected with current research assays (b). Intermittent viremia (blips) may occur due to stochastic surges in viral production and/or variation in assay performance near its limit of detection, and may be detected in both patient populations.

Figure 2. Strategies to purge the latent reservoir

(a) Class I selective histone deacetylase (HDAC) inhibitors inactivate HDACs 1, 2, and 3 at the human immunodeficiency virus (HIV) long-terminal repeat promoter (LTR). This allows unopposed activity of histone acetyltransferases (HAT), recruited to the LTR by transcription factors (TF), resulting in acetylation of histones at nucleosomes near the site of initiation of LTR transcription, and HIV expression. (b) Hexamethylene bisacetamide (HMBA) induces the release of positive transcription elongation factor (P-TEFb) from HMBA-induced protein 1 (HEXIM), leading to phosphorylation of RNA polymerase II (RNAP II) at the LTR and subsequent processive HIV transcription. (c) Cellular microRNAs (miRNA) in resting CD4+ T cells prevent the translation of HIV mRNA. Inhibition of these miRNAs with antisense miRNA inhibitors permits translation of the HIV proteins Tat and Rev, which translocate to the nucleus and facilitate HIV expression. (d) Cytosine residues at the LTR can be methylated by DNA methyltransferases (DNMT), a phenomenon associated with transcriptional silencing. The DNA methylation inhibitor 5-aza-2’ deoxycytidine (5-aza-dC) removes the methylation marks and can stimulate HIV expression. (e) Complexes at the enhancer sites of the LTR, such as C-promoter binding factor-1 (CBF-1), or the homodimeric p50 form of NF-κB may recruit HDACs during latency. In resting CD4+ T cells, the activating NF-κB heterodimer p50-p65 is sequestered in the cytoplasm. Prostratin induces the nuclear translocation of p50-p65 and the recruitment of HATs to the NF-κB binding sites on the LTR, resulting in HIV expression.