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

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/mm(3). HIV RNA was 5.5 log(10) copies/ml. Median total blood HIV DNA was higher in Fiebig III (550 copy/10(6) PBMC) vs. Fiebig I (8 copy/10(6) 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

Acute HIV infection detection and immediate treatment estimated to reduce transmission by 89% among men who have sex with men in Bangkok

Published 28 June 2017Introduction: Antiretroviral treatment (ART) reduces HIV transmission. Despite increased ART coverage, incidence remains high among men who have sex with men (MSM) in many places. Acute HIV infection (AHI) is characterized by high viral replication and increased infectiousness. We estimated the feasible reduction in transmission by targeting MSM with AHI for early ART. Methods: We recruited a cohort of 88 MSM with AHI in Bangkok, Thailand, who initiated ART immediately. A risk calculator based on viral load and reported behaviour, calibrated to Thai epidemiological data, was applied to estimate the number of onwards transmissions. This was compared with the expected number without early interventions. Results: Forty of the MSM were in 4th-generation AHI stages 1 and 2 (4thG stage 1, HIV nucleic acid testing (NAT)+/4thG immunoassay (IA)-/3rdG IA–; 4thG stage 2, NAT+/4thG IA+/3rdG IA–) while 48 tested positive on third-generation IA but had negative or indeterminate western blot (4thG stage 3). Mean plasma HIV RNA was 5.62 log¹⁰ copies/ml. Any condomless sex in the four months preceding the study was reported by 83.7%, but decreased to 21.2% by 24 weeks on ART. After ART, 48/ 88 (54.6%) attained HIV RNA <50 copies/ml by week 8, increasing to 78/87 (89.7%), and 64/66 (97%) at weeks 24 and 48, respectively. The estimated number of onwards transmissions in the first year of infection would have been 27.3 (95% credible interval: 21.7–35.3) with no intervention, 8.3 (6.4–11.2) with post-diagnosis behaviour change only, 5.9 (4.4–7.9) with viral load reduction only and 3.1 (2.4–4.3) with both. The latter was associated with an 88.7% (83.8–91.1%) reduction in transmission. Conclusions: Disproportionate HIV transmission occurs during AHI. Diagnosis of AHI with early ART initiation can substantially reduce onwards transmission.Eugène D.M.B. Kroon, Nittaya Phanuphak, Andrew J. Shattock, James L.K. Fletcher, Suteeraporn Pinyakorn, Nitiya Chomchey, Siriwat Akapirat, Mark S. de Souza, Merlin L. Robb, Jerome H. Kim, Frits van Griensven, Jintanat Ananworanich, and David P. Wilson on behalf of the RV254/SEARCH 010 Study Grou

Diagrammatic representation of the effect of a <i>cis</i> acting polymorphism upon allelic expression.

<p>Depicted is the situation for an individual who is heterozygous for a <i>cis</i> acting polymorphism with alleles A and C and is also heterozygous for a polymorphism within the affected transcript.</p

Deviation from a simple log normal distribution (Simulation parameters ).

<p>Panels A and B show the effects of outliers (). In panel A and in Panel B the outlier frequency, <i>p_out</i>, is 0.03: Panels C and D present the situation when the log of the expression of each allele follows a t-distribution with 2 degrees of freedom (C for and D for ).</p

Observed allelic expression ratios measured at rs5854, a transcribed polymorphism at the 3′ end of the MMP1 gene grouped according to the genotype for rs11292517, a polymorphism in the promoter region of the gene.

<p>Observed allelic expression ratios measured at rs5854, a transcribed polymorphism at the 3′ end of the MMP1 gene grouped according to the genotype for rs11292517, a polymorphism in the promoter region of the gene.</p

Experimental data sets.

a<p>: <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028636#pone.0028636-Rutter1" target="_blank">[32]</a>.</p>b<p>: <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028636#pone.0028636-Mei1" target="_blank">[33]</a>.</p

A visualisation of different approaches for testing an association between allelic expression and a biallelic polymorphism.

<p>The distribution of allelic expression ratios across a population is represented. We consider here two polymorphisms: a transcribed one, with alleles m and M, used to measure allelic expression; and a <i>cis</i> acting one with alleles c and C. Each elongated diamond represents the mean and the spread of the AEI measurements by specific genotypes. A) The general situation. B) Perfect disequilibrium (D′ = 1, R² = 1) between the <i>cis</i> acting and the transcribed polymorphism, only two distinct haplotypes exist. C) Complete disequilibrium (D′ = 1, R²<1), only three distinct haplotypes exist. D) Situation when the phase between alleles at both sites is known.</p

Summary of tests used.

a<p>: Pattern of disequilibrium, as represented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0028636#pone-0028636-g003" target="_blank">Figure 3</a>, for which the test is most appropriate.</p>b<p>: Assumes that given the genotype AERs follow a log normal distribution.</p