Increased CXCR4 Use of HIV-1 Subtype C Identified by Population Sequencing in Patients Failing Antiretroviral Treatment Compared with Treatment-Naive Patients in Botswana

Sollerkvist, Lotta Pramanik; Gaseitsiwe, Simani; Mine, Madisa; Sebetso, Gaseene; Mphoyakgosi, Thongbotho; Diphoko, Thabo; Essex, Max; Ehrnst, Anneka

doi:10.1089/aid.2013.0203

Cited by 4 publications

(9 citation statements)

References 256 publications

(461 reference statements)

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“…Some recent studies from South Africa and India also showed predominance of R5 strains in treatment naïve as well as experienced HIV-1C infected patients [12], although a South African study reported predominance of X4 strains in treatment experienced children [13]. More recently, a higher incidence of X4-tropic HIV-1C were described in patients with advanced immunodeficiency from South Africa, India and Botswana, respectively [14–17]. However, recent tropism data from patients with progressive HIV-1C ET infection is lacking.…”

Section: Introductionmentioning

confidence: 99%

Monophylogenetic HIV-1C epidemic in Ethiopia is dominated by CCR5-tropic viruses–an analysis of a prospective country-wide cohort

et al. 2017

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BackgroundCCR5 coreceptor using HIV-1 subtype C (HIV-1C) has been reported to dominate the Ethiopian epidemic. However, almost all data have been obtained from two large cities in the central and north-west regions and recent data is lacking.MethodsPlasma were obtained from 420 treatment-naïve patients recruited 2009–2011 to a large country-wide Ethiopian cohort. The V3 region was sequenced and the co-receptor tropism was predicted by the clinical and clonal models of the geno2pheno tool at different false positive rates (fpr) and for subtype. In an intention to treat analysis the impact of baseline tropism on outcome of antiretroviral therapy was evaluated.ResultsV3 loop sequencing was successful in 352 (84%) patients. HIV-1C was found in 350 (99.4%) and HIV-1A in two (0.6%) patients. When comparing the geno2pheno fpr10% clonal and clinical models, 24.4% predictions were discordant. X4-virus was predicted in 17.0 and 19.0%, respectively, but the predictions were concordant in only 6%. At fpr5%, concordant X4-virus predictions were obtained in 3.1%. The proportion of X4-tropic virus (clonal fpr10%) increased from 5.6 to 17.3% (p < 0.001) when 387 Ethiopian V3 loop sequences dated from 1984 to 2003 were compared with ours. In an intention to treat analysis, 67.9% reached treatment success at month 6 and only 50% at month 12. Only age and not tropism predicted therapy outcome and no difference was found in CD4+ cell gain between R5-tropic and X4-tropic infected patients. At viral failure, R5 to X4 switch was rare while X4 to R5 switch occurred more frequently (month 6: p = 0.006; month 12: p = 0.078).ConclusionThe HIV-1C epidemic is monophylogenetic in all regions of Ethiopia and R5-tropic virus dominates, even in patients with advanced immunodeficiency, although the proportion of X4-tropic virus seems to have increased over the last two decades. Geno2pheno clinical and clonal prediction models show a large discrepancy at fpr10%, but not at fpr5%. Hence further studies are needed to assess the utility of genotypic tropism testing in HIV-1C. In ITT analysis only age and not tropism influenced the outcome.

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Section: Introductionmentioning

confidence: 99%

Monophylogenetic HIV-1C epidemic in Ethiopia is dominated by CCR5-tropic viruses–an analysis of a prospective country-wide cohort

et al. 2017

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“…Viruses using the CXCR4 coreceptor are referred to as X4-tropic viruses. In some cases, viruses use both the CCR5 and the CXCR4 coreceptors (i.e., dual-tropic viruses) [ 3 ]. In the early stage of HIV-1, viruses predominantly use CCR5 but can switch to CXCR4 at an advanced stage of the disease [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…In the early stage of HIV-1, viruses predominantly use CCR5 but can switch to CXCR4 at an advanced stage of the disease [ 4 , 5 ]. CXCR4 usage increases among patients on antiretroviral treatment (ART) [ 3 , 6 , 7 ]. A coreceptor switch to CXCR4 is associated with higher pathogenicity and has been reported in ~50% of HIV-1 subtype B infections but is rare and under-studied in subtype C infection [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…One study focused on 148 ART-naïve women with advanced stage of disease (CD4 cell counts below 200 cells/mm 3 ) and found that ~15% of the women harbored HIV-1C dual-tropic viruses [ 13 ]. However, more recent studies have uncovered an increase in HIV-1C CXCR4 usage, which could reflect an evolving HIV-1C epidemic [ 3 , 15 , 16 , 17 ]. Among 24 treatment-experienced people living with HIV (PLWH) in Botswana in 2014, 33% had HIV-1C X4-tropic viruses based on Geno2pheno prediction [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Prediction of Coreceptor Tropism in HIV-1 Subtype C in Botswana

Kotokwe

Moyo

Zahralban-Steele

et al. 2023

Viruses

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It remains unknown whether the C-C motif chemokine receptor type 5 (CCR5) coreceptor is still the predominant coreceptor used by Human Immunodeficiency Virus-1 (HIV-1) in Botswana, where the HIV-1 subtype C predominates. We sought to determine HIV-1C tropism in Botswana using genotypic tools, taking into account the effect of antiretroviral treatment (ART) and virologic suppression. HIV-1 gp120 V3 loop sequences from 5602 participants were analyzed for viral tropism using three coreceptor use predicting algorithms/tools: Geno2pheno, HIV-1C Web Position-Specific Score Matrices (WebPSSM) and the 11/25 charge rule. We then compared the demographic and clinical characteristics of people living with HIV (PLWH) harboring R5- versus X4-tropic viruses using χ2 and Wilcoxon rank sum tests for categorical and continuous data analysis, respectively. The three tools congruently predicted 64% of viruses as either R5-tropic or X4-tropic. Geno2pheno and the 11/25 charge rule had the highest concordance at 89%. We observed a significant difference in ART status between participants harboring X4- versus R5-tropic viruses. X4-tropic viruses were more frequent among PLWH receiving ART (χ2 test, p = 0.03). CCR5 is the predominant coreceptor used by HIV-1C strains circulating in Botswana, underlining the strong potential for CCR5 inhibitor use, even in PLWH with drug resistance. We suggest that the tools for coreceptor prediction should be used in combination.

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“…A significant majority of the initial infecting HIV-1-C viruses utilize CCR5. However, the presence of a significant proportion of CXCR4 utilizing viruses (X4) in chronic HIV-1-C infection [32][33][34] might compromise the effectiveness of CCR5 antagonists, such as Maraviroc, when included as components in salvage therapy. In the current analyses, co-receptor preference in early and chronic HIV-1-C infections across Africa was examined, using sequences from the Los Alamos HIV Sequence Database, with the view of understanding the co-receptor preference landscape of the epidemiologically important HIV-1-C across the continent.…”

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confidence: 99%

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

Matume

Tebit

2020

AIDS Res Ther

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Background: Entry inhibitors, such as Maraviroc, hold promise as components of HIV treatment and/or pre-exposure prophylaxis in Africa. Maraviroc inhibits the interaction between HIV Envelope gp120 V3-loop and CCR5 coreceptor. HIV-1 subtype C (HIV-1-C) is predominant in Southern Africa and preferably uses CCR5 co-receptor. Therefore, a significant proportion of HIV-1-C CXCR4 utilizing viruses (X4) may compromise the effectiveness of Maraviroc. This analysis examined coreceptor preferences in early and chronic HIV-1-C infections across Africa.Methods: African HIV-1-C Envelope gp120 V3-loop sequences sampled from 1988 to 2014 were retrieved from Los Alamos HIV Sequence Database. Sequences from early infections (< 186 days post infection) and chronic infections (> 186 days post infection) were analysed for predicted co-receptor preferences using Geno2Pheno [Coreceptor] 10% FPR, Phenoseq-C, and PSSMsinsi web tools. V3-loop diversity was determined, and viral subtype was confirmed by phylogenetic analysis. National treatment guidelines across Africa were reviewed for Maraviroc recommendation.Results: Sequences from early (n = 6316) and chronic (n = 7338) HIV-1-C infected individuals from 10 and 15 African countries respectively were available for analyses. Overall, 518/6316 (8.2%; 95% CI 0.7-9.3) of early sequences were X4, with Ethiopia and Malawi having more than 10% each. For chronic infections, 8.3% (95% CI 2.4-16.2) sequences were X4 viruses, with Ethiopia, Tanzania, and Zimbabwe having more than 10% each. For sequences from early chronic infections (< 1 year post infection), the prevalence of X4 viruses was 8.5% (95% CI 2.6-11.2). In late chronic infections (≥ 5 years post infection), X4 viruses were observed in 36% (95% CI − 16.3 to 49.9), with two countries having relatively high X4 viruses: South Africa (43%) and Malawi (24%). The V3-loop amino acid sequence were more variable in X4 viruses in chronic infections compared to acute infections, with South Africa, Ethiopia and Zimbabwe showing the highest levels of V3-loop diversity. All sequences were phylogenetically confirmed as HIV-1-C and clustered according to their co-receptor tropism. In Africa, Maraviroc is registered only in South Africa and Uganda. Conclusions:Our analyses illustrate that X4 viruses are present in significantly similar proportions in early and early chronic HIV-1 subtype C infected individuals across Africa. In contrast, in late chronic infections, X4 viruses increase 3-5 folds. We can draw two inferences from our observations: (1) to enhance the utility of Maraviroc in chronic HIV subtype C infections in Africa, prior virus co-receptor determination is needed; (2) on the flip side, research on the efficacy of CXCR4 antagonists for HIV-1-C infections is encouraged. Currently, the use of Maraviroc is very limited in Africa.

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Increased CXCR4 Use of HIV-1 Subtype C Identified by Population Sequencing in Patients Failing Antiretroviral Treatment Compared with Treatment-Naive Patients in Botswana

Cited by 4 publications

References 256 publications

Monophylogenetic HIV-1C epidemic in Ethiopia is dominated by CCR5-tropic viruses–an analysis of a prospective country-wide cohort

Monophylogenetic HIV-1C epidemic in Ethiopia is dominated by CCR5-tropic viruses–an analysis of a prospective country-wide cohort

Prediction of Coreceptor Tropism in HIV-1 Subtype C in Botswana

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

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