Title:HIV Preintegration Transcription and Host Antagonism
Volume: 21
Issue: 3
Author(s): Yuntao Wu*
Affiliation:
- Center for Infectious Disease Research, George Mason University, Manassas, Virginia, United States
Keywords:
HIV unintegrated DNA, preintegration transcription, chromatin, histone deacetylase inhibitor, Nef, Tat, Rev, Vpr.
Abstract: Retrovirus integration is an obligatory step for the viral life cycle, but large amounts of
unintegrated DNA (uDNA) accumulate during retroviral infection. For simple retroviruses, in the
absence of integration, viral genomes are epigenetically silenced in host cells. For complex retroviruses
such as HIV, preintegration transcription has been found to occur at low levels from a large
population of uDNA even in the presence of host epigenetic silencing mechanisms. HIV preintegration
transcription has been suggested to be a normal early process of HIV infection that leads to the
syntheses of all three classes of viral transcripts: multiply-spliced, singly-spliced, and unspliced genomic
RNA; only viral early proteins such as Nef are selectively translated at low levels in blood
CD4 T cells and macrophages, the primary targets of HIV. The initiation and persistence of HIV
preintegration transcription have been suggested to rely on viral accessory proteins, particularly virion
Vpr and de novo Tat generated from uDNA; both proteins have been shown to antagonize host
epigenetic silencing of uDNA. In addition, stimulation of latently infected resting T cells and macrophages
with cytokines, PKC activator, or histone deacetylase inhibitors has been found to greatly
upregulate preintegration transcription, leading to low-level viral production or even replication
from uDNA. Functionally, Nef synthesized from preintegration transcription is biologically active
in modulating host immune functions, lowering the threshold of T cell activation, and downregulating
surface CD4, CXCR4/CCR5, and HMC receptors. The early Tat activity from preintegration
transcription antagonizes repressive minichromatin assembled onto uDNA. The study of HIV preintegration
transcription is important to understanding virus-host interaction and antagonism, viral
persistence, and the mechanism of integrase drug resistance. The application of unintegrated lentiviral
vectors for gene therapy also offers a safety advantage for minimizing retroviral vector-mediated
insertional mutagenesis.
