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

Two theories to explain 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.

Phylogenetic analysis of plasma and reservoir sequences from a patient on HAART illustrating the presence of a PPC. The figure shows a phylogenetic tree of pol gene sequences from free virus in the plasma (triangles) and cerebrospinal fluid (CSF) (inverted triangles) and from provirus in resting CD4⁺ T cells (circles), activated CD4⁺ T cells (diamonds), monocytes (hexagons), and unfractionated PBMCs (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. See details in Bailey et al.²⁰

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 2 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. FI, Fusion inhibitor; II, integrase inhibitor.