Early ART Intervention Restricts the Seeding of the HIV Reservoir in Long-lived Central Memory CD4 T Cells
Jintanat Ananworanich*1,2,3,4, C Vandergeeten5, N Chomchey1,2, N Phanuphak1,2, V Ngauy6, R-P Sekaly5, M Robb7, N Michael7, J Kim1,7, N Chomont5, and RV254/SEARCH 010 Study Group
1SEARCH, Bangkok, Thailand; 2The Thai Red Cross AIDS Res Ctr, Bangkok; 3HIVNAT, Bangkok, Thailand; 4Faculty of Med, Chulalongkorn Univ, Bangkok, Thailand; 5Vaccine and Gene Therapy Inst, Port St Lucie, FL, US; 6Armed Forces Res Inst of Med Sci, Bangkok, Thailand; and 7US Military HIV Res Prgm, Silver Spring, MD
Background: HIV infection of central memory CD4 T cells (TCM) is a major cause of HIV persistence and an obstacle to HIV cure. Acute HIV infection (AHI) represents a window of opportunity to intervene to limit reservoir seeding.
Methods: 47 subjects with Fiebig stages I to III were enrolled (stage I: NAT+, p24-, 3rd generation EIA-; stage II: p24+, 3rd gen EIA-; stage III: 3rd gen EIA+/WB-). Total and integrated HIV DNA was measured in peripheral blood mononuclear cells (PBMC) (n = 47) and sigmoid colon (n = 21) by real-time PCR (detection limit 3 copies/106 cells). HIV DNA was determined in CD4 T cell populations of a subset who had leukapheresis. Subjects initiated ART at a median of 2 (IQR 1-3) days from baseline. Mann-Whitney U test was used to determine differences in HIV DNA between Fiebig stages and Spearman's rank test was used to assess correlation between reservoir localization at weeks 0 and 24.
Results: At baseline, Fiebig stages (subjects) were I (19), II (3), and III (25). Median (IQR) total peripheral blood mononuclear cell (PBMC) HIV DNA content was lower in Fiebig I (7, 0-32) than Fiebig II (2191, 96-4042) and Fiebig III (289, 40-1062), p = 0.0002. All Fiebig I subjects had undetectable integrated DNA compared with 33% and 52% of Fiebig II and III subjects, respectively. In 3 Fiebig I and 4 Fiebig II/III subjects undergoing leukapheresis, most integrated HIV DNA was seeded in CD4 T cells, and not monocytes, B or CD8 T cells. Importantly, the 3 Fiebig I subjects had no detectable integrated DNA in TCM, TTM, and TEM. Among 4 Fiebig II-III subjects, all showed low infection in TCM with median integrated DNA copies/106 cells of 446 (342-774) for TCM, 2830 (987-6485) for TTM and 1898 (780-3461) for TEM. After 24 weeks of ART, HIV integrated DNA was dramatically reduced in all with 100% Fiebig I (n = 11), 67% Fiebig II (n = 3), and 72% Fiebig III (n = 18) having undetectable levels. The localization of the reservoir at week 0 predicts the localization after treatment (Correlation coefficient: 0.89, p-value <0.0001). In sigmoid colon (8 Fiebig I, 11 Fiebig II/III), median HIV integrated DNA copies/106 cells were 0 in Fiebig I, 9263 in Fiebig II, and 149 in Fiebig III, p = 0.01. After 24 weeks of ART, 100% Fiebig I (n = 4) and 67% Fiebig II/III (n = 9) had undetectable HIV integrated DNA.
Conclusions: Fiebig I subjects exhibited extremely low reservoir size with no detected HIV integrated DNA in PBMC and memory CD4 T cell subsets before and after ART. Early ART intervention restricted the seeding of the HIV reservoir in long-lived TCM.