Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection.

Jintanat Ananworanich,Mark De Souza,Irini Sereti,Nittaya Phanuphak,Robert Paris,Frits Van Griensven,Robin Dewar,Jerome H Kim,Victor Valcour,Rungsun Rerknimitr,Nelson Michael,Praphan Phanuphak,Frank Maldarelli,Rapee Trichavaroj,Alexandra Schuetz,Claire Vandergeeten,Suteeraporn Pinyakorn,Mary Marovich,Nitiya Chomchey,Nicolas Chomont,Wiriya Rutvisuttinunt,Sheila A Peel ,Rafick Pierre Sékaly

doi:10.1371/journal.pone.0033948

Abstract

BackgroundLimited knowledge exists on early HIV events that may inform preventive and therapeutic strategies. This study aims to characterize the earliest immunologic and virologic HIV events following infection and investigates the usage of a novel therapeutic strategy.Methods and FindingsWe prospectively screened 24,430 subjects in Bangkok and identified 40 AHI individuals. Thirty Thais were enrolled (8 Fiebig I, 5 Fiebig II, 15 Fiebig III, 2 Fiebig IV) of whom 15 completed 24 weeks of megaHAART (tenofovir/emtricitabine/efavirenz/raltegravir/maraviroc). Sigmoid biopsies were completed in 24/30 at baseline and 13/15 at week 24.At baseline, the median age was 29 years and 83% were MSM. Most were symptomatic (87%), and were infected with R5-tropic (77%) CRF01_AE (70%). Median CD4 was 406 cells/mm3. HIV RNA was 5.5 log10 copies/ml. Median total blood HIV DNA was higher in Fiebig III (550 copy/106 PBMC) vs. Fiebig I (8 copy/106 PBMC) (p = 0.01) while the median %CD4+CCR5+ gut T cells was lower in Fiebig III (19%) vs. Fiebig I (59%) (p = 0.0008).After 24 weeks of megaHAART, HIV RNA levels of <50 copies were achieved in 14/15 in blood and 13/13 in gut. Total blood HIV DNA at week 0 predicted reservoir size at week 24 (p<0.001). Total HIV DNA declined significantly and was undetectable in 3 of 15 in blood and 3 of 7 in gut. Frequency of CD4+CCR5+ gut T cells increased from 41% at baseline to 64% at week 24 (p>0.050); subjects with less than 40% at baseline had a significant increase in CD4+CCR5+ T cells from baseline to week 24 (14% vs. 71%, p = 0.02).ConclusionsGut T cell depletion and HIV reservoir seeding increases with progression of AHI. MegaHAART was associated with immune restoration and reduced reservoir size. Our findings could inform research on strategies to achieve HIV drug-free remission.

Highlights

Three decades after the discovery of antiretroviral therapy (ART), complete eradication of HIV infection has not been achieved except under unique circumstances [1]
MegaHAART was associated with immune restoration and reduced reservoir size
Symptomatic acute HIV infection (AHI), sometimes referred to as acute retroviral syndrome (ARS), is characterized by a flu-like syndrome that coincides with peak HIV viremia, and occurs around three weeks after infection [5]

Summary

Introduction

Three decades after the discovery of antiretroviral therapy (ART), complete eradication of HIV infection has not been achieved except under unique circumstances [1]. Preservation of immune function by preventing the CD4 depletion in acute HIV infection (AHI), which occurs prominently in the gut, may be a prerequisite to achieving functional cure [2]. Data on immunologic and virologic events as early as Fiebig stages I to III in humans infected with HIV are lacking; yet, such knowledge could inform the design of preventive HIV vaccines and therapeutics [5,6]. Symptomatic AHI, sometimes referred to as acute retroviral syndrome (ARS), is characterized by a flu-like syndrome that coincides with peak HIV viremia, and occurs around three weeks after infection [5]. Limited knowledge exists on early HIV events that may inform preventive and therapeutic strategies. This study aims to characterize the earliest immunologic and virologic HIV events following infection and investigates the usage of a novel therapeutic strategy

Objectives

Methods

Results

Discussion

Conclusion