Abstract
BackgroundDuring HIV-1 infection coreceptor switch from CCR5- (R5)- to CXCR4 (X4)-using viruses is associated with disease progression. X4 strains of HIV-1 are highly cytopathic to immature thymocytes. Virtually no studies have evaluated the HIV-1 quasispecies present in vivo within thymic and lymphoid tissues or the evolutionary relationship between R5 and X4 viruses in tissues and peripheral blood.Methodology/Principal FindingsHigh-resolution phylodynamic analysis was applied to virus envelope quasispecies in longitudinal peripheral blood mononuclear cells (PBMCs) and lymphoid and non-lymphoid tissues collected post mortem from therapy naïve children with AIDS. There were three major findings. First, continued evolution of R5 viruses in PBMCs, spleen and lymph nodes involved multiple bottlenecks, independent of coreceptor switch, resulting in fitter quasispecies driven by positive selection. Second, evolution of X4 strains appeared to be a sequential process requiring the initial fixation of positively selected mutations in V1-V2 and C2 domains of R5 variants before the emergence of high charge V3 X4 variants. Third, R5 viruses persisted after the emergence of CXCR4-using strains, which were found predominantly but not exclusively in the thymus.Conclusions/SignificanceOur data indicate that the evolution of X4 strains is a multi-step, temporally structured process and that the thymus may play an important role in the evolution/amplification of coreceptor variants. Development of new therapeutic protocols targeting virus in the thymus could be important to control HIV-1 infection prior to advanced disease.
Highlights
Infection of target cells by human immunodeficiency virus type 1 (HIV-1) requires binding of the viral surface protein gp120 to the cellular surface protein CD4 and chemokine receptors CCR5 or CXCR4 [1]
Our study included detailed mapping of the evolutionary patterns of HIV-1 virodemes in blood, as well as lymphoid and nonlymphoid tissues, and applied phylogenetic and population genetic tools to examine the dynamics of virus interaction within the host
Most studies have focused almost exclusively on the V3 loop as the genetic marker, while none tested for positive selection in the internal branches of reconstructed genealogies, which is a hallmark of ancestral episodic selection leading to adaptive response [48]
Summary
Infection of target cells by human immunodeficiency virus type 1 (HIV-1) requires binding of the viral surface protein gp120 to the cellular surface protein CD4 and chemokine receptors CCR5 or CXCR4 [1]. X4 viruses using the CXCR4 coreceptor appear at a later stage in about 50% of individuals infected by HIV-1 subtype B and are associated with accelerated disease progression [4,5]. During HIV-1 infection coreceptor switch from CCR5- (R5)- to CXCR4 (X4)-using viruses is associated with disease progression. Evolution of X4 strains appeared to be a sequential process requiring the initial fixation of positively selected mutations in V1-V2 and C2 domains of R5 variants before the emergence of high charge V3 X4 variants. Development of new therapeutic protocols targeting virus in the thymus could be important to control HIV-1 infection prior to advanced disease
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