Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection

Although highly active antiretroviral therapy (HAART) can reduce HIV-1 viremia to levels that are below the limit of detection of clinical assays, the virus persists in reservoirs, and trace levels of free virions can be found in the plasma. Whether this residual viremia represents ongoing cycles of replication continuing despite HAART or simply the release of virus from stable reservoirs has been controversial. Here we summarize the evidence that HAART can stop ongoing cycles of replication. The evidence comes from a detailed analysis of the residual viremia, which shows it to be archival and nonevolving in character. In addition, new pharmacodynamic measures incorporating a previously ignored slope parameter have provided the first real indication of how well HAART actually suppresses viral replication in vivo. Together, these results argue that the ultimate theoretical potential of HAART to control viral replication has already been reached. Progress toward eradication of the infection will require novel approaches to target the stable reservoirs that persist even when viral replication is completely halted.

Key words: HAART, latency, reservoir, antiretroviral drug, residual viremia, slope, eradication

Abbreviations used: D, Drug concentration, HAART, Highly active antiretroviral therapy, IC₅₀, Drug concentration that inhibits the maximum effect by 50%, IIP, Instantaneous inhibitory potential, m, Slope parameter, NNRTI, Nonnucleoside reverse transcriptase inhibitor, NRTI, Nucleoside analogue reverse transcriptase inhibitor, PI, Protease inhibitor, PPC, Predominant plasma clone, RV, Residual viremia