Viral Dynamics in HIV-1 Infection

Abstract

A great deal of progress has been made in understanding the molecular biology of HIV-1 replication (see reviews by Cullen 1998, Chan and Kim 1998, Littman 1998 in this issue of Cell). Nevertheless, critical aspects of AIDS pathogenesis remain to be elucidated. For example, it is still unclear how HIV-1 infection induces CD4+ T cell depletion, which is the central pathophysiologic feature of the disease. It is also uncertain how the virus persists in the presence of vigorous immune responses. Recently, important insights into these complex aspects of the host–pathogen interaction in HIV-1 infection have come from a surprisingly simple approach, the direct measurement of circulating levels of free virus. The development of rapid, sensitive, and accurate methods for quantitating virus particles in the blood has greatly facilitated the study of AIDS pathogenesis and the management of patients with HIV-1 infection. Quantitative competitive RT-PCR is carried out on blood and other biological fluids to detect genomic viral RNA, which is present at two copies per virion (Piatak et al. 1993). Because the rate of clearance of free virus from the blood is largely independent of stage of disease and other factors, the level of viral RNA in the plasma reflects the rate of virus production. Recent studies suggest that the half-life of free virus particles is extremely short, on the order of minutes to hours (Perelson et al. 1996). Thus, the steady-state level of viral RNA genomes in the blood reflects very recent virus production. As a result, physicians and investigators in this field have a tool that is available for few other infectious diseases, a real-time measure of the rate of replication of the pathogen in the host. Analysis of dynamic changes in the level of plasma virus at different stages of disease and in response to antiretroviral therapy has provided some startling new insights into the mechanism of CD4+ T cell depletion, the reasons for drug failure, the nature of viral reservoirs, and the intriguing possibility that prolonged therapy may lead to virus eradication. The measurement of viral dynamics in vivo is a new area of study, made possible by the availability of assays for free virus and of antiretroviral drugs that perturb the steady-state equilibrium between virus production and virus clearance. It is likely that lessons learned will have broad-reaching influence on the study of other infectious diseases. This review will discuss recent advances in the study of viral dynamics, focusing on the possibility of HIV-1 eradication with antiretroviral therapy.