A new test developed at the University of Massachusetts Medical School and the Hammersmith Hospital in London could help researchers identify HAART regimens which can truly halt HIV replication in the body, according to a report in the January 2000 edition of Nature Medicine.
Using a technique which looks for waste products from HIV replication, the group found that 76% of individuals with viral load below 50 copies had evidence of ongoing viral replication, despite having no detectable HIV according to the most sensitive tests currently in use.
The group looked at 63 patients on HAART from Worcester, Massachusetts, and the Chelsea and Westminster Hospital in London. All had viral load below 400 copies, and 24 had viral load below 50 copies. All except three were receiving triple or quadruple therapy.
The technique looks for circles of DNA from HIV's long terminal repeat (LTR) region. These circles are created in the nucleus of a white blood cell which has just been infected by HIV (an activated T-lymphocyte), and differ from those found in resting CD4 cells, so a test which can detect the LTR circles will demonstrate whether ongoing HIV infection of new cells is taking place.
Although the researchers speculate that ongoing virus replication is being driven by virus production in tissues which cannot be penetrated by current treatments, they admit that there is no evidence from their study to support this view, and further research will be required to identify any reservoirs of virus production that remain after apparently successful HIV suppression on HAART.
The technique is likely to help researchers identify whether new regimens can switch off virus replication in the reservoirs and whether it might be possible to eradicate HIV from the body. In a report published in the same issue of Nature Medicine, David Ho and colleagues report that their recent pessimism about the time it might take for HIV to be cleared from the reservoir of resting T-lymphocytes may be a consequence of the inability of current regimens to maintain persistent viral suppression.
"Our results challenge the idea of a lifelong persistence of a pool of latent HIV-1", Ho said. In 1998 Ho and colleagues were forced to admit that they had been over-optimistic about the prospects of HIV eradication after a number of research groups, including their own, found that latent HIV was not decaying as quickly as early predictions had suggested, and that a latent reservoir of HIV might take 80 years to disappear if the infected cells died off at a similar rate to that observed in the first few years of HAART.
The Aaron Diamond Centre group reports that only 12 of 30 patients in their trials who experienced a reduction in viral load below 50 copies were able to maintain undetectable viral load. There was a significant relationship between the number of times viral load `blipped' above 50 copies and the size of the HIV-infected resting T-lymphocyte population. On average, individuals in the study experienced three blips during the course of the year.
There did not appear to be any significant difference in adherence between the two groups, nor any evidence of emerging resistance. The researchers conclude that current therapies are simply not powerful enough to keep HIV under control, and that future regimens will need to be more powerful, with the ability to penetrate into any reservoirs currently untouched by HAART.
Ramratnam B et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nature Medicine 6:1, 82-85, 2000.
Sharkey M et al. Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy. Nature Medicine 6:1, 76-81, 2000.