Study Sheds Light on Residual Viral Load

SUMMARY Residual low-level HIV plasma viremia correlates with size of the CD4 T-cell reservoir, but not immune activation markers.

By Liz Highleyman

Residual amounts of HIV genetic material can be detected in most people with HIV even after many years on effective combination antiretroviral therapy (ART). Viral DNA, or provirus, can remain latent inside resting CD4 T-cells, as well as anatomic areas such as the brain and gut, creating a reservoir that is impervious to current antiretroviral drugs.

But these cells can become activated in various ways, causing latent HIV to start replicating again. This is why even people with "undetectable" viral load must remain on treatment. Various strategies towards a cure for HIV aim to activate resting T-cells in order to purge or flush out the virus.

As described in the July 1, 2011, Journal of Infectious Diseases, Tae-Wook Chun and Anthony Fauci from the National Institute of Allergy and Infectious Diseases and colleagues looked at associations between residual plasma viremia, CD4 cell reservoir size, and levels of immune activation.

As previously described, Chun and Fauci's team has carried out some key studies in the area of HIV latency. In the mid-1990s they started treating a small cohort of patients whose HIV infection was diagnosed very early. Based on the half-life of latently infected CD4 T-cells and the decay of plasma HIV levels, they suggested that people who start treatment during primary infection might eliminate all virus in resting CD4 cells with 7.7 years of ART.

More recently, however, Chun and colleagues reported that while patients who started ART early had significantly less HIV DNA in their resting CD4 T-cells than those who started treatment later, all still had a small amount of residual virus, and even 1 patient with an extremely low level still experienced viral rebound after an experimental ART interruption.

In the present study the researchers assessed plasma viremia using very sensitive tests that could measure down to 0 copies/mL. They tested samples from 127 participants on ART who had undetectable plasma viral load for extended periods, as measured by standard clinical assays (limit of detection of 50 copies/mL). They used an automated system that ran the tests in quadruplicate for each individual.

Results

	63% of participants with "undetectable" viral load < 50 copies/mL had detectable plasma viremia (1-49 copies/mL) according to the sensitive tests.
	37% had no measurable plasma HIV RNA.
	The median residual viremia level was 2.7 copies/mL.
	Residual plasma HIV level correlated with the size of the CD4 T-cell viral reservoir, or cells carrying proviral DNA.
	Individuals with undetectable plasma viremia according to the sensitive tests had fewer CD4 cells carrying HIV DNA, on average, than those with detectable plasma viremia.
	Residual plasma viremia did not, however, correlate with markers of immune activation including C-reactive protein, D-dimer, interleukin 6, soluble TNF receptor I, and CD38 expression on CD4 and CD8 T-cells.

These findings, the study authors wrote, suggest that "reactivation of the latent viral reservoir may not be the sole source of residual plasma viremia."

Residual viremia "may also originate from productively infected CD4+ T-cells in various lymphoid tissues," they proposed, noting that "it is possible to have low levels of viral replication and cell-to-cell spread of virus, particularly in lymphoid organs, without such replication being reflected in the levels of plasma viremia, even as measured by the most sensitive assays."

If this is the case, they concluded, activating resting T-cells may not be enough to get rid of the virus, and "[n]ovel therapeutic strategies aimed at targeting the source of residual viremia may be necessary to achieve viral eradication."

"Achieving eradication of HIV in infected individuals receiving ART remains a daunting challenge for the scientific community," they continued in their discussion. "To achieve a functional cure, as defined by the absence of detectable HIV for extended periods of time in the absence of ART, therapeutic strategies aimed at eliminating cellular reservoirs in various tissue compartments must be accompanied by comprehensive virological assays that monitor infected CD4+ T-cells that may or may not contribute to residual plasma viremia."

Investigator affiliations: Laboratory of Immunoregulation, and Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; Department of Medicine, University of Toronto, Ontario, Canada.

7/5/11

Reference
TW Chun, D Murray, JS Justement, et al. Relationship Between Residual Plasma Viremia and the Size of HIV Proviral DNA Reservoirs in Infected Individuals Receiving Effective Antiretroviral Therapy. Journal of Infectious Diseases 204(1):135-138 (abstract). July 1, 2011.