515 T-cell Subset Perturbations During the First Interruption Phase of Subjects Treated During Primary HIV Infection: Activation and CCR5 Expression Correlate with Viral Load J. Zaunders*1, M. Munier2, P. Cunningham1, D. Smith2, P. Grey2, D. Quan3, R. McFarlane4, A. Kelleher2, D. A. Cooper2 1St Vincent's Hosp, Sydney, Australia; 2Natl Ctr In HIV Epidemiology Clin Res, Sydney, Australia; 3Holdsworth House Gen Practice, Sydney, Australia; and 4407 Doctors, Sydney, Australia
Background: Changes in CD4 and CD8 T-cell subsets during primary HIV infection (PHI) have been inferred from cross-sectional studies of symptomatic subjects at presentation. However, little is known about events in the very early period leading up to onset of symptoms. Prospective study of changes occurring during interruptions to therapy may provide insight into perturbations occurring very early in the infection.
Methods: Subjects were enrolled in the PULSE trial of treatment interruption following 32-52 weeks of therapy with 3TC/ddI/IDV/RTV ±HU, commenced in PHI. All patients had plasma HIV RNA < 50 copies/ml, and weekly blood samples were obtained prior to and during 4 wks of interruption. Naïve, memory, activated (CD38+HLA-DR+), proliferating (Ki-6 7+), coreceptor CCR5+, and spontaneously apoptotic T-cell subsets were analyzed by flow cytometry.
Results: Seven (7) subjects had viral rebounds within 2-3 weeks (high rebound group; median 53,000 copies/ml at wk 4), while 8 subjects had little or no rebound (low rebound group; median 1000 copies/ml at wk 4). High rebound subjects showed a slight decrease in total CD4 T-lymphocytes from median 737-582 cells/µl (mean decrease: 94 cells/µl). Slight decreases were seen in both the naïve and memory subsets (median decreases of 38 and 7 cells/µl, with nadirs at wks 4 and 2, respectively). The CD8 count rose from a median of 627 to a peak of 836 cells/µl, entirely due to a rapid increase in the activated subset, from 57-309 cells/µl between wks 2 and 3. The peak of activated CD8 T-cells coincided with a plateau of viral load, and was associated with increased proliferation rate in vivo and spontaneous apoptosis rate in vitro. Furthermore, activation and increased CCR5 co-receptor expression on both CD4 and CD8 T-cells was highly correlated with increased viral load. By comparison, the 8 subjects with low rebounds had a mean CD4 count decrease of 75 cells/µl, but had minimal change in CD8 subsets or CCR5 levels.
Conclusions: T-cell subset changes resulting from re-initiation of viral replication were not as dramatic as seen in PHI, but included a late increase in activated, proliferating, spontaneously apoptotic CD8 T-cells. Importantly, there appeared to be a very close association between HIV viral load, activation, and increased CCR5 expression, which may represent a major factor in the establishment of chronic replicative infection.
