Viral load increases in cells predicts CD4 cell decline in asymptomatic patients

Viral load increases steadily in cells during the asymptomatic stage of HIV infection, and is an accurate marker of disease progression, Dutch investigators report in the online edition of AIDS. They found that increases in HIV RNA and DNA in peripheral blood mononuclear cells (PBMC) were correlated with the loss of CD4 cells.

However, there was no association between CD4 cell decline and plasma viral load.

“We have shown that HIV-1 (especially HIV-1 usRNA level) in PBMC is a more direct and sensitive marker of the infection progression in the asymptomatic phase than the viral load in plasma,” comment the investigators, who add, “this observation…positions the HIV-1 usRNA in PBMCs as a unique laboratory marker that may, in several aspects, perform better than ‘traditional’ plasma viral RNA load.”

Many patients with HIV have an asymptomatic phase. This is characterised by a slow decline in CD4 cell count. Plasma viral load during this phase, however, remains stable, only increasing significantly before the onset of AIDS.

Dutch investigators wished to see if the dynamics of HIV viral load in cells during the asymptomatic phase could be tied to CD4 cell decline.

They developed sensitive methods of measuring three measures of viral load in this PBMCs: HIV proviral (pr) DNA, unsliced (us) RNA and multiply-spliced (ms) RNA.

Changes in these three measures of viral load in cells were monitored overtime in ten HIV-positive gay men, all of whom were infected with HIV-1 subtype-B and were in the asymptomatic phase of the infection. None was taking antiretroviral therapy.

Trends cell viral load were correlated with changes in CD4 cell count, and the investigators also undertook analyses to see if increases in plasma viral load could be related to falls in CD4 cell count.

A total of 53 measurements of viral load in PBMCs were available for analysis. Each of these was accompanied by a CD4 cell count, and 51 were also matched with a plasma viral load.

The investigators found that plasma viral load did not change significantly over time.

However, there were statistically significant increases in usRNA in the PBMCs of six patients, and in four individuals prDNA increased significantly in cells. In five individuals, there was a significant fall in CD4 cell count.

Significant changes from baseline were observed in usRNA and prDNA in PBMCs, and CD4 cell count (p < 0.001). However, no significant increase was recorded in plasma viral load.

The investigators noted a significant relationship between increases in usRNA (p = 0.006) and prDNA (p = 0.02) in cells and a fall in CD4 cell count. Once again, no relationship was found between plasma viral load and CD4 cell changes.

Despite the significance of their findings, the investigators caution that “participants were followed for different periods and as the observation periods were not synchronized with respect to time to time from seroconversion, these longitudinal trends, in the strict sense, should not be interpreted as reflecting the natural history of HIV viremia. Ideally, generalization of our findings requires a larger study with patients followed from seroconversion until the onset of clinical symptoms of AIDS.”

Nevertheless, they believe that their results “indicate that the HIV-1 replication rates in PBMCs during the asymptomatic phase directly correlate with the state of the immune system.”