S16   Host Factors in the Pathogenesis of HIV Disease: Implications for Therapeutic Strategies

Anthony S. Fauci
NIAID, NIH, Bethesda, MD

Recent work in our laboratory has examined the relationship between host factors and latent reservoirs of replication-competent HIV, including long-lived "resting" CD4+ T cells. Over the past year, it has become evident that 1) viral reservoirs persist in HIV-infected individuals despite long periods of aviremia on highly active antiretroviral therapy (HAART); 2) HIV persistently replicates, even in patients whose levels of plasma virus have fallen below detectable levels while on HAART; and 3) numerous short- and long-term toxicities are associated with HAART. It is highly unlikely that HIV can be eradicated with currently available therapies, and HIV-infected individuals face the prospect of many years - or a lifetime - of continuous HAART. Therefore, a number of approaches that may reduce a patient’s reliance on HAART are being pursued for the long-term control of HIV disease. Among these are variations on the theme of strategically interrupting therapy. In acutely infected individuals, recent data indicate that strategic therapy interruptions are associated with a likely enhancement of the immunological responses that could control viremia. With chronically infected individuals, who may have substantial immune system damage, the situation is somewhat different. In this patient group, a number of structured therapy interruption protocols have focused on the concept of allowing the virus to rebound and “autovaccinate” against the virus, thereby enhancing the immune system. Generally these protocols resume therapy after interruption only when plasma virus rises to pre-determined levels. We have taken a somewhat different approach, in which patients discontinue and resume therapy at pre-determined times: either two months on therapy followed by one month off; or seven days on therapy followed by seven days off. The goal of this approach, called “structured intermittent therapy,” is to reduce the total time on HAART The results of these two studies will be discussed in detail, together with the pathophysiological relevance of interruption of therapy, the return of viremia, and enhancement of immunological responses.&tab;