CCR5- and CXCR4-utilizing strains of human immunodeficiency virus type 1 exhibit differential tropism and pathogenesis in vivo.
CCR5-utilizing (R5) and CXCR4-utilizing (X4) strains of human immunodeficiency virus type 1 (HIV-1) have been studied intensively in vitro, but the pathologic correlates of such differential tropism in vivo remain incompletely defined. In this study, X4 and R5 strains of HIV-1 were compared for tropism and pathogenesis in SCID-hu Thy/Liv mice, an in vivo model of human thymopoiesis. The X4 strain NL4-3 replicates quickly and extensively in thymocytes in the cortex and medulla, causing significant depletion. In contrast, the R5 strain Ba-L initially infects stromal cells including macrophages in the thymic medulla, without any obvious pathologic consequence. After a period of 3 to 4 weeks, Ba-L infection slowly spreads through the thymocyte populations, occasionally culminating in thymocyte depletion after week 6 of infection. During the entire time of infection, Ba-L did not mutate into variants capable of utilizing CXCR4. Therefore, X4 strains are highly cytopathic after infection of the human thymus. In contrast, infection with R5 strains of HIV-1 can result in a two-phase process in vivo, involving apparently nonpathogenic replication in medullary stromal cells followed by cytopathic replication in thymocytes.
Berkowitz
R D
RD
Gladstone Institute of Virology and Immunology, San Francisco, Stanford University, Stanford, and Veterans Hospital, Palo Alto, California, USA.
Alexander
S
S
Bare
C
C
Linquist-Stepps
V
V
Bogan
M
M
Moreno
M E
ME
Gibson
L
L
Wieder
E D
ED
Kosek
J
J
Stoddart
C A
CA
McCune
J M
JM
D000818:Animals; D003588:Cytopathogenic Effect, Viral; D015658:HIV Infections / Q000209:etiology / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000473:pathology / Q000821:virology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009154:Mutation; D019713:Receptors, CCR5 / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000502:physiology*; D017154:Stromal Cells / Q000473:pathology / Q000821:virology; D013601:T-Lymphocytes / Q000473:pathology / Q000821:virology; D013950:Thymus Gland / Q000473:pathology / Q000821:virology; D014774:Virulence; D014779:Virus Replication
D019713:Receptors, CCR5; D019718:Receptors, CXCR4