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

Abstract

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.

Figure 1.

Two theories to RV in patients on HAART. (A) RV represents ongoing cycles of replication that continue at a lower level because of the suppressive effects of the drugs. (B) HAART stops all ongoing cycles replication, and the RV reflects release of virus from stable reservoirs such as the latent reservoir in resting CD4⁺ T cells.

Figure 2.

Phylogenetic analysis of plasma and reservoir sequences from a patient on HAART illustrating the presence of a predominant plasma clone (PPC). The figure shows a phylogenetic tree of pol gene sequences from free virus in the plasma (triangles) and CSF (inverted triangles) and from provirus in resting CD4⁺ T cells (circles), activated CD4⁺ T cells (diamonds), monocytes (hexagons), and unfractionated PBMC (squares). Colors indicate sampling times. Note the repeated isolation of a PPC sequence over a 2 year period. This same sequence was profoundly underrepresented among resting CD4⁺ T cells. For details, see reference 20.

Figure 3.

Clinical concentrations of some antiretroviral drugs cause profound inhibition of viral replication as a result of high slope values. (A) Hypothetical dose-response curves for two antiviral drugs with the same IC₅₀ but different slope values. The response is plotted as f_u, the percent of infection events that are unaffected by a given concentration of drug. For drugs with an m value of 1, the dose-response curves are shallow, and the degree of inhibition achieved in the clinical concentration range (shaded area, 10–100 times the IC₅₀) is limited. For a drug with an m value of 3 and the same IC₅₀, 10,000 fold greater inhibition is achieved at C_max. (B) IIP of current antiretroviral drugs at C_max plotted on the same scale as in (A). Note that for some PIs, IIP is on the order of 10 logs, a 10,000,000,000 fold inhibition of replication.