Persistent HIV Viremia Fosters Immunologic Harm and Viral Evolution

By David Douglas

Persistent low-level HIV viremia is associated with ongoing immune activation and antiretroviral treatment failure, according to a report in the April 30th issue of AIDS.

In untreated HIV infection, HIV replication, HIV-specific T-cell responses, and T-cell activation contribute to disease outcome, the authors explain. How these factors interact in the setting of antiretroviral therapy is not well understood.

Dr. Steven G. Deeks from University of California, San Francisco, and colleagues assessed HIV-specific CD8 T-cell responses, T-cell activation, and phenotypic drug susceptibility during a longitudinal study of treated HIV-infected individuals experiencing sustained viral suppression, intermittent viremia, or persistent low-level viremia.

Ten of 18 patients with persistent low-level viremia experienced virologic failure during the median 27 months of follow-up, the authors report, compared with 8 of the 15 patients with intermittent viremia and none of the 13 patients with sustained suppression.

The HIV-specific T-cell response was 12-fold greater among patients with persistent low-level viremia and 9.5-fold greater among patients with intermittent viremia than among patients with sustained viral suppression, the report indicates. Patients with intermittent or persistent viremia also showed a greater breadth of HIV-specific immune responses than did patients with sustained suppression.

HIV-specific T-cell responses were stable over time in patients with suppressed and persistent viremia, the researchers note, whereas the responses rose and fell with HIV RNA levels in patients with intermittent viremia.

The median level of activated CD8 T cells was substantially higher in patients with persistent viremia (16%) than in patients with suppressed or intermittent viremia (6% and 9%, respectively), the investigators report. Most patients with persistent low-level viremia also experienced an increase in the level of drug resistance under stable therapy.

"Our study suggests that persistent HIV replication during therapy drives 'generalized' immune activation, and that the activated immune system in turn supports viral evolution and a greater risk of virologic rebound," Dr. Deeks told Reuters Health. "In contrast, brief or transient periods of HIV replication does not have a measurable impact on immune activation. Thus, our data suggest that short-term exposures to a vaccine will not be harmful."

"Ongoing work in our group is focusing on the nature of these activated T cells," Dr. Deeks added. "We are particularly interested in the antigenic specificity of these cells. We are also interested in the question as to why some individuals exhibit high level immune activation during HIV infection while others do not."

"Although our study focused on HIV pathogenesis in the setting of highly effective antiretroviral therapy, we believe that our data have direct clinical implications," Dr. Deeks said. "For example, low level viral replication-as defined by persistent levels of detectable HIV RNA-is associated with immunologic harm and ongoing viral evolution. Such individuals may require a treatment modification."

"Also, our data suggest that specific immunomodulators during incompletely suppressive therapy may prove to be very useful," Dr. Deeks said. "My hope is to see such drugs developed for this purpose."

AIDS 2004;18:981-989.