Persistent HIV viraemia fosters immunologic harm and viral evolution
David Douglas, HIVandHepatits.com
Persistent low-level HIV viraemia is associated with ongoing immune activation and antiretroviral treatment failure, according to a report in the 30 April 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 the 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 viraemia, or persistent low-level viraemia.
Ten of 18 patients with persistent low-level viraemia experienced virologic failure during the median 27 months of follow-up, the authors report, compared with 8 of the 15 patients with intermittent viraemia 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 viraemia and 9.5-fold greater among patients with intermittent viraemia than among patients with sustained viral suppression, the report indicates. Patients with intermittent or persistent viraemia 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 viraemia, the researchers note, whereas the responses rose and fell with HIV RNA levels in patients with intermittent viraemia.
The median level of activated CD8 T cells was substantially higher in patients with persistent viraemia (16%) than in patients with suppressed or intermittent viraemia (6% and 9%, respectively), the investigators report. Most patients with persistent low-level viraemia also experienced an increase in the level of drug resistance under stable therapy.
“Our study suggests that persistent HIV replication during therapy drives ‘generalised’ 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 do 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.”
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Increasing or persistent levels of virus activity are likely to induce T cell responses. However knowing that these responding T cells can express IFN-gamma is not enough. It is important we know more about the quality of those responses i.e. not just their antigen specificity but the degree to which they can perform effector functions such as cellular proliferation, IL-2 production and cytotoxic perforin release.
It would appear that the HIV-specific IFN-gamma responses detected in this study show as little correlation with protection from viral activity as those described by Walker and Autran (see Keystone Report, this issue of HTB).
Karlsson AC, Younger SR, Martin JN et al. Immunologic and virologic evolution during periods of intermittent and persistent low-level viraemia. AIDS. 2004 Apr 30;18(7):981-9.