Phylodynamics of HIV-1 in lymphoid and non-lymphoid tissues reveals a central role for the thymus in emergence of CXCR4-using quasispecies.
BACKGROUND
During 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.


RESULTS
High-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
Our 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.
Salemi
Marco
M
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida, USA. salemi@pathology.ufl.edu
Burkhardt
Brant R
BR
Gray
Rebecca R
RR
Ghaffari
Guity
G
Sleasman
John W
JW
Goodenow
Maureen M
MM
D002648:Child; D002675:Child, Preschool; D015686:Gene Products, env / Q000235:genetics; D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000145:classification / Q000235:genetics; D015658:HIV Infections / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism / Q000821:virology; D008221:Lymphoid Tissue / Q000378:metabolism / Q000821:virology; D010802:Phylogeny; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic / Q000235:genetics; D013950:Thymus Gland / Q000378:metabolism* / Q000821:virology
D015686:Gene Products, env; D015699:HIV Envelope Protein gp120; D019718:Receptors, CXCR4; C514793:gp120 protein, Human immunodeficiency virus 1