Low viral loads in elite controllers

Several years ago, Bruce Walker and colleagues from Partners AIDS Research in Boston launched the largest ever effort to research immunological control of HIV infection, the international HIV controllers study. [1]

The project is now proceeding under the aegis of the new Ragon Institute of Massachusetts General Hospital, created recently thanks to the generous support of the Ragon family. [2]

The HIV controllers study is collecting blood samples from both elite controllers, defined based on having a viral load less than 50 copies in the absence of any treatment, and viremic controllers, defined based on a viral load of between 50 and 2000 copies/mL in the absence of treatment. A number of papers have been published already describing results from the study, and the latest has just appeared online in the Journal of Infectious Diseases.

The purpose of this investigation was to quantify the level of viral load among elite controllers using an ultra-sensitive assay that can measure down to a single copy/mL of HIV RNA. [3]

Among 90 individuals studied, the median viral load level was 2 copies/mL. A longitudinal analysis of a subset of 31 participants demonstrated that 2-5-fold fluctuations in viral load were common. For the first time, the researchers were also able to document a significant inverse correlation between the breadth and potency of neutralising antibody responses against HIV and the level of viral load detected; previous studies using less sensitive viral load assays did not reveal this association. The breadth and magnitude of HIV-specific CD8 cell responses, as measured solely by interferon-gamma production, did not show a correlation with viral load at these low levels.

An analysis of the relationship between viral load and the slope of CD4 decline was also conducted. The median time for which multiple CD4 measurements were available was 3.6 years (range 1 17.3), and the median number of measurements per person was seven. Although immune activation has previously been associated with CD4 cell declines in elite controllers, [4] in this analysis the median value of the slope per year was +11 cells/mm3.

Due the limited duration of follow up and number of measurements, the researchers note that in many cases the values were not significantly different from zero, indicating CD4 T cell counts were essentially stable over time. To try and get a better sense of which participants might be experiencing significant changes in CD4 counts, the researchers subsequently focused on individuals whose slopes were statistically different from zero. These analyses revealed that 5 out of 27 individuals (19%) with viral load levels less than 1 copy/mL experienced significant CD4 cell count increases over time. The same was true for only 3 out of 50 individuals (3%) with HIV viral loads greater than 1 copy/mL. Conversely, 8 individuals experienced significant CD4 cell declines, and all showed viral load levels over 1 copy/mL. An overall examination of the link between viral load level and CD4 cell count slope showed a weak but significant correlation, with higher viral loads associated with CD4 cell decline (r=-0.23; p=0.04).

Overall, the results suggest that the use of a viral load assay that is 250-fold more sensitive than those currently commercial available can reveal important information regarding elite control of HIV.