Steve Deeks and others reported that they examined the correlates of a sustained CD4 response after virologic failure of a protease inhibitor (PI) based regimen using measures of viral fitness, lymphocyte cycling and lymphocyte activation.

This is a cross-sectional study of 3 groups of subjects: virologic responders (sustained viral load < 50 copies/mL on a PI-based regimen) [n=13]; virologic non-responders (sustained viral load > 2500 copies/mL on a PI-based regimen) [n=24], and untreated patients [n=12]. All patients had a CD4 nadir < 300. Viral fitness was measured using recombinant HIV-1 vectors expressing patient derived PR-RT and containing a luciferase indicator gene (this assay is similar to the PhenoSense drug susceptibility assay except that read-out is normalized for viral inoculum, and no anti-retroviral drugs are used).

Median viral load for the virologic responders, non-responders and untreated controls was 1.7, 4.3 and 4.8 log10 copies RNA/ml. Non-responders had experienced virologic failure for a median of 26.8 months, had a CD4 T-cell count 119 cells above pre-therapy nadir, and had a mean 58-fold decrease in phenotypic susceptibility to their PI therapy. The median replication fitness value, defined as relative light count production, was 0.2 (IQR 0.14, 0.40) for virologic non-responders and 1.2 (1.18, 1.42) for untreated patients [p = 0.0001]. For the virologic responders, non-responders and untreated patients respectively, the percent of CD4 expressing Ki67 was 2.3, 4.3 and 8.7 (p = 0.02), and the percent of CD4 expressing activation markers (CD38, HLA-DR) was 3.1, 8.9 and 14.8 (p = 0.001). Among non-responders, both %Ki67+ and %CD38+DR+ were positively correlated with viral load (rho = 0.45, p = 0.02 and rho = 0.4, p = 0.04 respectively).

Replication of recombinant viruses expressing protease and reverse transcriptase derived from a group of subjects with prolonged virologic failure and highly resistant virus was markedly diminished. Taken as a whole, these data suggest that decreased replication capacity may preserve CD4 cells count by decreasing virus replication, T-cell activation and T-cell turnover.