Residual viremia (RV) is present in most if not all patients who are responding well to highly activeantiretroviral therapy (HAART). It now appears that HAART reduces viremia to new steady state level thataverages around 1 copy of HIV-1 RNA/ml of plasma. This steady state appears to persist indefinitely with nofurther decay. Because the half life of virions in the plasma is short (minutes to hours), the continuedpresence of free virus in the plasma of patients on HAART indicates ongoing virus production. Thus it isclear that the sources of RV must be understood if HIV-1 eradication is to be achieved. In the previousfunding period, we have carried out the first study of intensification of a standard HAART regimen. Wefound that intensification fails to reduce RV, indicating that most of the RV results from release of virus fromstable reservoirs of cells infected prior to the initiation of therapy. These results indicate that the theoreticalpotential of HAART to control viremia has already been reached and that further progress towards HIVeradication will require new strategies that directly target stable reservoirs. Through the clonal analysis ofRV, we have also found that the RV there is at least one other source of RV in addition to the stablereservoir in resting CD4+ T cells. We now propose to continue studies of RV to obtain clones of replication-competent virus from the RV. This will provide direct evidence that the viruses constituting the RV are ofpotential clinical significance. In addition, in a new project prompted by the interest in our intensificationstudy, we will study patients who have stable low level viremia in the range of 75-400 copies/ml. Thesepatients currently represent a significant clinical dilemma. The presence of detectable viremia often triggersa change in regimen. However, it is possible that stable low level viremia reflects release of virus from stablereservoirs that are larger in some patients than in others. Thus we will carry out a detailed analysis of lowlevel viremia in these patients in order to provide a molecular explanation for persistent low level viremia andto obtain additional insight into stable viral reservoirs.

Public Health Relevance

;Most pafients who are doing well on combination therapy for HIV infection have trace levels of free virus inthe blood called residual viremia. We have shown that this residual viremia is due to the release of virusfrom stable reservoirs of infected cells that persist despite the presence of antiretroviral drugs. Progresstowards HIV eradication will require the identification and elimination of these reservoirs.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Salzwedel, Karl D
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Johns Hopkins University
Internal Medicine/Medicine
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