Longitudinal analysis of HIV-1 coreceptor tropism by single and triplicate HIV-1 RNA and DNA sequencing in patients undergoing successful first-line antiretroviral therapy

Abstract

ObjectivesMaraviroc has been shown to be effective in patients harbouring CCR5-tropic HIV-1. While this CCR5 antagonist has initially been used in salvage therapy, its excellent safety profile makes it ideal for antiretroviral treatment simplification strategies in patients with suppressed plasma viraemia. The aim of this study was to compare HIV-1 tropism as detected in baseline plasma RNA and peripheral blood mononuclear cell (PBMC) DNA prior to first-line therapy and to analyse tropism evolution while on successful treatment.MethodsHIV-1 tropism was determined using triplicate genotypic testing combined with geno2pheno[coreceptor] analysis at a 10% false positive rate in 42 patients. Paired pre-treatment plasma RNA and PBMC DNA and two subsequent PBMC DNA samples (the first obtained after reaching undetectable plasma HIV-1 RNA and the second after at least 2 years of suppression of plasma viraemia) were evaluated.ResultsCoreceptor tropism was completely concordant in paired pre-treatment RNA and DNA, with 26.2% of HIV-1 sequences predicted to be non-CCR5-tropic. During follow-up, coreceptor tropism switches were detected in 4 (9.5%) patients without any preferential direction. Although false positive rate discrepancies within triplicates were common, the rate of discordance of coreceptor tropism assignment among triplicate results in this mostly CCR5-tropic dataset was only 2.1%, questioning the added value of triplicate testing compared with single testing.ConclusionsHIV-1 coreceptor tropism changes during virologically successful first-line treatment are infrequent. HIV-1 DNA analysis may thus support the choice of a CCR5 antagonist in treatment switch strategies; however, maraviroc treatment outcome data are required to confirm this option.

Determination of HIV-1 coreceptor tropism using proviral DNA in women before and after viral suppression

“…A potential explanation for this phenomenon could be low level viral replication that was below the limit of quantitation (80 copies/mL) of the plasma viral load assays used in the WIHS. It is also consistent with some viral replication persisting in cells during viral suppression in plasma [ 21 , 26 ]. Clonal expansion of latently infected cells during suppressive ART has also been described [ 27 ].…”

“…This phenomenon could potentially alter the proportion of non-R5 virus over prolonged periods of virologic suppression. Two other studies that investigated tropism evolution in suppressed patients found lower rates of tropism switching of 7.1% (N = 128, median suppression 4 years) [ 28 ] and 9.5% respectively (N = 42, median suppression 2 years) [ 21 ]. These studies however, were performed on more recently supressed patients, used a viral load cutoff of 50 copies/mL and included both male and female subjects.…”

“…A number of studies have shown strong agreement between plasma RNA and pvDNA tropism [ 16 - 20 ]. However, few studies have examined pvDNA tropism longitudinally in individuals taking suppressive ART [ 21 - 23 ], and most previous studies of HIV-1 tropism have focused mostly on men [ 4 , 8 , 12 , 16 ].…”

HIV-1 subtype C predicted co-receptor tropism in Africa: an individual sequence level meta-analysis

“…However, as disease progresses, CXCR4 utilizing viruses emerge in about 50% of infected individual [41][42][43]. By Variation at the GPGQ Crown motif (%) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 and large, in Africa Maraviroc is prescribed mostly for patients who have failed first and second line regimens, which are comprised of nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors [44,45]. Since, HIV-1-C drives the epidemic in Southern Africa and accounts for about 46% of infections worldwide [24], the current investigation was aimed at determining the distribution of R5 and X4 viruses in early versus chronic infections in HIV-1-C acquired through MTCT and heterosexual routes in Africa.…”

Caracterização molecular da gp120 do HIV-1 e suas implicações sobre o tropismo pelos correceptores CCR5 e CXCR4

“…Vários estudos foram realizados para avaliar o uso de DNA a partir de células monucleares do sangue periférico (PMBCs) para testes de tropismo genotípico. A concordância entre resultados de RNA de HIV-1 plasmático e DNA proviral de PMBCs variou de 85% a 100%, demonstrando a contemporaneidade entre as populações virais nestes espécimes, no contexto de tropismo viral (Meini et al, 2014;Paar et al, 2011;Prosperi et al, 2010;Saracino et al, 2007). Verificouse, ainda, que a produção de vírus R5 e X4 e as subpopulações virais encontradas no sangue periférico são produzidas por células com duração de vida semelhantes e não são geneticamente isoladas de um tipo particular de células (Ince et al, 2009).…”