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

Abstract

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.

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

“…In our study, the HIV-1C tropism trends are analysed from a larger dataset in Botswana of more than 5000 sequences over a period of 5 years (2013–2018). Our current study captures a more accurate current picture of the HIV-1C tropism trends in the Botswana epidemic when compared to the Matume et al [ 36 ] study. Their study only analysed 1401 sequences from Botswana over a wider time period, inclusive of previous Botswana cohorts from a wider timeline highlighted by [ 3 , 11 , 13 ].…”

“…Phenotyping testing is also recommended. Other clinical parameters should also be taken into account, consistent with previous studies’ suggestion of administering alternative drug regimens before considering Maraviroc [ 36 ]. If the participant has gone through all possible options of combination ART and is in need of salvage therapy, we recommend the use of Maraviroc alongside other salvage therapy drugs in Botswana.…”

“…Botswana HIV-1 prevalence is among the highest in the world at 20.3% in 2018 [ 20 ]. Monitoring coreceptor usage is vital, as the emergence of X4-tropic viruses in chronic HIV-1 infections [ 36 ] affects the suitability of third-line drugs, such as Maraviroc, for PLWH who experience multi-drug or multi-class resistance. In this study, we utilized seven tools for prediction of HIV-1 tropism in 5602 people living with HIV-1C in Botswana.…”

“…Furthermore, we found no difference in coreceptor usage in the early and chronic stages of infection (< or >1 year). In contrast, an African meta-analysis of coreceptor tropism found a 3-5-fold increase in X4-tropic viruses during chronic infection [ 36 ]. The disparity is likely due to the difference in the definition of chronic stage, as HIV-1 infections ≥5 years were classified as chronic in the meta-analysis [ 36 ], while we defined chronic infections as >1 year, based on the data available.…”

“…In contrast, an African meta-analysis of coreceptor tropism found a 3-5-fold increase in X4-tropic viruses during chronic infection [ 36 ]. The disparity is likely due to the difference in the definition of chronic stage, as HIV-1 infections ≥5 years were classified as chronic in the meta-analysis [ 36 ], while we defined chronic infections as >1 year, based on the data available. Therefore, the majority of chronic infections in our study were more recent than those in the meta-analysis.…”