Coreceptor tropism in human immunodeficiency virus type 1 subtype D: high prevalence of CXCR4 tropism and heterogeneous composition of viral populations.
In human immunodeficiency virus type 1 (HIV-1) subtype B, CXCR4 coreceptor use ranges from approximately 20% in early infection to approximately 50% in advanced disease. Coreceptor use by non-subtype B HIV is less well characterized. We studied coreceptor tropism of subtype A and D HIV-1 collected from 68 pregnant, antiretroviral drug-naive Ugandan women (HIVNET 012 trial). None of 33 subtype A or 10 A/D-recombinant viruses used the CXCR4 coreceptor. In contrast, nine (36%) of 25 subtype D viruses used both CXCR4 and CCR5 coreceptors. Clonal analyses of the nine subtype D samples with dual or mixed tropism revealed heterogeneous viral populations comprised of X4-, R5-, and dual-tropic HIV-1 variants. In five of the six samples with dual-tropic strains, V3 loop sequences of dual-tropic clones were identical to those of cocirculating R5-tropic clones, indicating the presence of CXCR4 tropism determinants outside of the V3 loop. These dual-tropic variants with R5-tropic-like V3 loops, which we designated "dual-R," use CCR5 much more efficiently than CXCR4, in contrast to dual-tropic clones with X4-tropic-like V3 loops ("dual-X"). These observations have implications for pathogenesis and treatment of subtype D-infected individuals, for the association between V3 sequence and coreceptor tropism phenotype, and for understanding potential mechanisms of evolution from exclusive CCR5 use to efficient CXCR4 use by subtype D HIV-1.
Huang
Wei
W
Monogram Biosciences, 345 Oyster Point Blvd., South San Francisco, CA 94080, USA. whuang@monogrambio.com
Eshleman
Susan H
SH
Toma
Jonathan
J
Fransen
Signe
S
Stawiski
Eric
E
Paxinos
Ellen E
EE
Whitcomb
Jeannette M
JM
Young
Alicia M
AM
Donnell
Deborah
D
Mmiro
Francis
F
Musoke
Philippa
P
Guay
Laura A
LA
Jackson
J Brooks
JB
Parkin
Neil T
NT
Petropoulos
Christos J
CJ
D000465:Algorithms; D000595:Amino Acid Sequence; D005260:Female; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism; D014644:Genetic Variation; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D010641:Phenotype; D010802:Phylogeny; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000821:virology; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D019562:Viral Load
D015686:Gene Products, env; D019713:Receptors, CCR5; D019718:Receptors, CXCR4