ANALYSIS OF COVERT VIRAL REPLICATION DURING HAART

Project: Research project

Project Details

Description

Anti-retroviral drug combinations currently used for the treatment
of HIV- 1 infection potently suppress plasma HIV- 1 RNA to below detectable
levels. Although this suppression can be maintained over prolonged periods,
viral replication rapidly rebounds in individuals who discontinue therapy. The
ability of HIV-1 to persist in the face of highly active anti-retroviral
therapy (HAART) has been attributed to the presence of a reservoir of latently
infected cells that rekindles virus replication following therapy interruption.
However, even in well-suppressed patients, there is evidence of viral sequence
evolution, which suggests that there may be on going viral replication. The
examination of viral reservoirs in suppressed, aviremic patients is hampered by
a Jack of assays that are able to discriminate between latent infection and
on-going replication. As a consequence, the extent of viral replication that
persists in the face of HAART and the reservoir that supports it is poorly
understood.

Following infection of the cell, viral reverse transcription leads to the
synthesis of a full-length linear cDNA that circularize to form episomes
containing either one LTR (l-LTR circle) or 2 LTRs (2-LTR circle). We have
recently demonstrated that 2-L1'R circles are highly labile and, as such,
represent a specific marker for a recent infection event. We have developed a
quantitative 2-LTR circle assay and have demonstrated that these circles
persist in a large percentage of infected individuals on HAART with sustained
undetectable levels of plasma viral RNA. This suggests the presence of a
reservoir of "covert" virus replication that may allow the virus to persist in
the face of HAART. We propose to use this 2-LTR circle assay to understand the
basis for viral persistence in the face of HAART and to identify reservoirs for
covert viral replication. Specifically, we propose to

Aim 1: Evaluate the half-life of 2-LTR circles in primary cell types in vitro

Aim 2: Examine stability of 2-LTR circles in vivo and identify reservoirs for
covert viral replication during HAART

Aim 3: Longitudinally examine 2-LTR circle copy number in patients on HAART in
order to evaluate the decay characteristics of the persistent viral reservoir

These studies may shed further light on the underlying mechanism which allows
viral persistence in the face of HAART and may provide an approach to allow
monitoring of' the effectiveness of antiretroviral suppression when plasma
viral RNA assays are negative.
StatusFinished
Effective start/end date2/1/011/31/05

Funding

  • National Institute of Allergy and Infectious Diseases: $318,000.00
  • National Institute of Allergy and Infectious Diseases: $274,021.00
  • National Institute of Allergy and Infectious Diseases: $318,000.00
  • National Institute of Allergy and Infectious Diseases: $276,792.00

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