Abstract
ObjectiveThe association between emergence of CXCR4-tropic HIV-1 variants (X4 variants) and disease progression of HIV-1 infection has been reported. However, it is not known whether the emergence of X4 variants is the cause or result of HIV-1 disease progression. We tried to answer this question.DesignHIV-1 env sequences around the V3 region were analyzed in serially stocked samples in order to determine whether X4 variants emerged before or after the fall in CD4+ T-cell count.MethodsThe study subjects were five HIV-1-infected hemophiliac slow progressors. Deep sequencing around the HIV-1 env V3 region was conducted in duplicate. Tropism was predicted by geno2pheno [coreceptor] 2.5 with cutoff value of false positive ratio at <5%. When X4 variant was identified in the latest stocked sample before the introduction of antiretroviral therapy, we checked viral genotype in previously stocked samples to determine the time of emergence of X4 variants.ResultsEmergence of X4 variants was noted in two of the five patients when their CD4+ T-cell counts were still high. The rate of decrease of CD4+ T-cell count or of rise of HIV-1 load accelerated significantly after the emergence of X4 variants in these two cases. Phylogenetic analysis showed that these X4 variants emerged from CCR5-tropic HIV-1 viruses with several amino acid changes in the V3 region.ConclusionsThe emergence of X4 variants preceded HIV-1 disease progression in two hemophiliac slow progressors.
Highlights
Tropism of HIV-1 is defined by the usage of coreceptor on human cells, and has been considered to be associated with disease progression [1]
When X4 variant was identified in the latest stocked sample before the introduction of antiretroviral therapy, we checked viral genotype in previously stocked samples to determine the time of emergence of X4 variants
Many studies have reported that primary HIV-1-infected patients mainly have CCR5-tropic HIV-1 viruses (R5 viruses) while about half of the patients in the late stage of HIV-1 infection have both R5 viruses and CXCR4-tropic HIV-1 variants (X4 variants) [2]
Summary
Tropism of HIV-1 is defined by the usage of coreceptor on human cells, and has been considered to be associated with disease progression [1]. The association between emergence of X4 variants and rapid reduction of CD4+ T-cell counts has been reported [3,4,5,6,7,8]. Evidence suggests that X4 variants have a more potent ability to destroy the immune system because they have higher replication capacity in some cells and a wider range of host cells than R5 viruses [1,14,15]. The natural course of tropism change has been well studied [7,16,17,18], it is not clear yet whether the emergence of X4 variants is a cause or result of falling CD4+ T-cell count [2]
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