Abstract
Our objective was to analyze the evolution of resistance mutations (RM) and viral tropism of multi-drug-resistant (MDR) strains detected at primary HIV-1 infection (PHI). MDR HIV strain was defined as the presence of genotypic resistance to at least 1 antiretroviral of the 3 classes. Tropism determinations (CCR5 or CXCR4) were performed on baseline plasma HIV-RNA and/or PBMC-HIV-DNA samples, then during follow-up using population-based sequencing of V3 loop and phenotypic tests. Clonal analysis was performed at baseline for env, RT and protease genes, and for HIV-DNA env gene during follow-up. Five patients were eligible. At baseline, RT, protease and env clones from HIV-RNA and HIV-DNA were highly homogenous for each patient; genotypic tropism was R5 in 3 (A,B,C) and X4 in 2 patients (D,E). MDR strains persisted in HIV-DNA throughout follow-up in all patients. For patient A, tropism remained R5 with concordance between phenotypic and genotypic tests. Clonal analysis on Month (M) 78 HIV-DNA evidenced exclusively R5 (21/21) variants. In patient B, clonal analysis at M36 showed exclusively R5 variants (19/19) using both genotypic and phenotypic tests. In patient C, baseline tropism was R5 by genotypic test and R5/X4 by phenotypic test. An expansion of these X4 clones was evidenced by clonal analysis on M72 HIV-DNA (12/14 X4 and 2/14 R5 variants). In patient D, baseline tropism was X4 with concordance between both techniques and HIV-RNA and HIV-DNA remained X4-tropic up to M72, confirmed by the clonal analysis. Patient E harboured highly homogenous X4-using population at baseline; tropism was unchanged at M1 and M18. In all patients, the initial MDR population was highly homogenous initially, supporting the early expansion of a monoclonal population and its long-term persistence. X4-tropic variants present at baseline were still exclusive (patients D and E) or dominant (at least one time point, patient C) far from PHI.
Highlights
Sexual transmission of HIV-1 resistant strains has been well documented [1]
For patient A, harbouring a CCR5 strain at baseline, viral tropism determined by whole population sequencing was unchanged in peripheral blood mononuclear cells (PBMC) at Month 36 (M36) and M78
This is the first study providing longitudinal data on both resistance mutational pattern and viral tropism of circulating and archived viral strains in patients infected with a MDR HIV-1 as soon as primary HIV infection
Summary
The frequency of strains harbouring resistance to at least one antiretroviral drug at the time of primary HIV-1 infection (PHI) is stable in Europe over the last decade and reaches approximately 10–12% [2,3,4,5]. Transmission of X4-tropic HIV-1 strains at the time of PHI has been documented, and the prevalence of X4 strains at the time of PHI reaches approximately 15% [9,10,11]. Our objective was to characterize intracellular HIV-DNA in patients with a MDR HIV-1 strain detected at the time of PHI and to analyze the viral tropism in such patients. We analysed the temporal evolution of resistance patterns and viral tropism in plasma virions and in intracellular HIV-DNA extracted from peripheral blood mononuclear cells (PBMC). To analyze extensively the viral tropism, we performed a clonal analysis at baseline and during the follow-up and we classified the virus as X4 or R5 using both genotypic and phenotypic methods
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