Conference on Retroviruses and Opportunistic Infections (CROI 2013)
Paper #47 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 Group1SEARCH, 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.
News from hivandhepatitis.com
Starting antiretroviral therapy (ART) very early may restrict the size of the established HIV reservoir in long-lived T-cells, which could ultimately make it easier to achieve a functional cure, according to research presented last week at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) in Atlanta.
Jintanat Ananworanich from SEARCH and the Thai Red Cross AIDS Research Center in Bangkok and colleagues looked at the relationship between Fiebig stage — a classification system for staging early HIV infection — and levels of HIV DNA in peripheral blood cells and gut tissue. They found that people at the earliest stages of infection had extremely low reservoir size, and that starting treatment this early appears to restrict “seeding” of long-lived central memory T-cells.
Reference: J Ananworanich,C Vandergeeten, N Chomchey, et al. Early ART Intervention Restricts the Seeding of the HIV Reservoir in Long-lived Central Memory CD4 T Cells. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 47.
Bangkok Post (http://www.bangkokpost.com/lite/topstories/340779/red-cross-hails-hiv-trial-result)
Red Cross hails HIV trial result
HIV-positive patients have a high chance of a “functional cure” if they receive antiretroviral drugs within two weeks of infection, according to initial findings of a Thai Red Cross Society (TRCS) research project.
The TRCS unveiled the finding yesterday as it reported on the progress of its HIV/Aids research project called “Search 010”. A total of 96 people participated in the project, which started in 2009. Under the project, doctors gave antiretroviral drugs to 26 people, who had been infected with the HIV virus for no longer than two weeks, Jintanat Ananworanich, the project’s head researcher said. Blood tests taken after the patients had taken the drugs for two weeks found 24 participants, or 92%, had no HIV virus in their white blood cells, Dr Jintanat said. “However, that doesn’t mean there is zero virus in their body. They still have the virus, but at a safe level under a so-called functional cure,” she said. A functional cure is when the virus is reduced to such low levels that it is kept at bay even without continuing treatment. Among patients who received antiretroviral drugs after being infected with the virus for longer than two weeks, only 53% were found with no HIV virus in their white blood cells. The researchers are looking into whether the virus increases in a group of early-diagnosed patients who stop taking the drugs for five years. “If the viral load is still kept at bay, it means patients who receive early treatment can live a normal life without having to take antiretroviral drugs,” Dr Jintanat said.
