One of the most controversial questions in the field of HIV research is whether current antiretroviral therapy (ART) combinations maximally suppress viral replication. New technologies have allowed researchers to detect down to just 1 copy of HIV RNA per mL of blood and, even when the viral load is undetectable on commercially available tests (which typically can only detect 50 copies or more), most people on ART have a few copies of HIV RNA detectable in their samples. These HIV RNA copies could either be the product of ongoing rounds of viral replication (in which infected cells release new viruses that go on to infect other cells), or alternatively they could be produced by long-lived chronically infected cells. In the latter scenario, ART would prevent the newly-produced virus from being able to infect any other cells, but the drugs would not be able to eliminate the chronically infected cell.
Over the past few years, scientists have debated – often quite heatedly – which of these possibilities is true. Recent evidence has generally favored the view that, in most cases, ART is maximally suppressing HIV replication; for example, a study of viral evolution in people undergoing intermittent ART interruption found no evidence of ongoing viral evolution during the periods when participants were on therapy.
A study just published in PNAS tackles the question another way, by investigating whether intensifying ART by adding new drugs has an effect on residual viral load. Out of 15 total participants, only 9 consistently showed HIV RNA levels above 1 copy/mL prior to ART intensification (median 3 copies/mL). The highest level detected was around 30 copies/mL. The researchers found that ART intensification had no effect on these residual viral levels, indicating a lack of ongoing HIV replication. The results add to the evidence that low-level HIV RNA detectable in people on ART does not derive from ongoing viral replication, but rather a stable reservoir of infected cells. The major implication is that, in order to cure HIV infection, new strategies are needed to identify and eliminate this reservoir. PNAS has designated the paper "Open Access," click on the title link for the PDF.
Published online before print May 22, 2009, doi: 10.1073/pnas.0903107106
J. B. Dinoso a,b,1, S. Y. Kim a,1, A. M. Wiegand c, S. E. Palmer c,2, S. J. Gange d, L. Cranmer a, A. O'Shea e, M. Callender a, A. Spivak a, T. Brennan a, M. F. Kearney c, M. A. Proschan f, J. M. Mican g, C. A. Rehm g, J. M. Coffin c,h,3, J. W. Mellors i, R. F. Siliciano a,j and F. Maldarelli c,3
Departments of a Medicine and b Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;
c HIV Drug Resistance Program, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702;
d Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205;
e Critical Care Medicine Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892;
f Biostatistics Research Branch and g Division of Clinical Research, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892;
h Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111;
i Department of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and
j Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
1 J.B.D. and S.Y.K. contributed equally to this work.
In HIV-1-infected individuals on currently recommended antiretroviral therapy (ART), viremia is reduced to <50 copies of HIV-1 RNA per milliliter, but low-level residual viremia appears to persist over the lifetimes of most infected individuals. There is controversy over whether the residual viremia results from ongoing cycles of viral replication. To address this question, we conducted 2 prospective studies to assess the effect of ART intensification with an additional potent drug on residual viremia in 9 HIV-1-infected individuals on successful ART. By using an HIV-1 RNA assay with single-copy sensitivity, we found that levels of viremia were not reduced by ART intensification with any of 3 different antiretroviral drugs (efavirenz, lopinavir/ritonavir, or atazanavir/ritonavir). The lack of response was not associated with the presence of drug-resistant virus or suboptimal drug concentrations. Our results suggest that residual viremia is not the product of ongoing, complete cycles of viral replication, but rather of virus output from stable reservoirs of infection.