CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1-infected individuals.
The basis for the extensive variability seen in the reconstitution of CD4(+) T cell counts in HIV-infected individuals receiving highly active antiretroviral therapy (HAART) is not fully known. Here, we show that variations in CCL3L1 gene dose and CCR5 genotype, but not major histocompatibility complex HLA alleles, influence immune reconstitution, especially when HAART is initiated at <350 CD4(+) T cells/mm(3). The CCL3L1-CCR5 genotypes favoring CD4(+) T cell recovery are similar to those that blunted CD4(+) T cell depletion during the time before HAART became available (pre-HAART era), suggesting that a common CCL3L1-CCR5 genetic pathway regulates the balance between pathogenic and reparative processes from early in the disease course. Hence, CCL3L1-CCR5 variations influence HIV pathogenesis even in the presence of HAART and, therefore, may prospectively identify subjects in whom earlier initiation of therapy is more likely to mitigate immunologic failure despite viral suppression by HAART. Furthermore, as reconstitution of CD4(+) cells during HAART is more sensitive to CCL3L1 dose than to CCR5 genotypes, CCL3L1 analogs might be efficacious in supporting immunological reconstitution.
Ahuja
Sunil K
SK
Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, 7400 Merton Minter, San Antonio, Texas 78229, USA. ahujas@uthscsa.edu
Kulkarni
Hemant
H
Catano
Gabriel
G
Agan
Brian K
BK
Camargo
Jose F
JF
He
Weijing
W
O'Connell
Robert J
RJ
Marconi
Vincent C
VC
Delmar
Judith
J
Eron
Joseph
J
Clark
Robert A
RA
Frost
Simon
S
Martin
Jeffrey
J
Ahuja
Seema S
SS
Deeks
Steven G
SG
Little
Susan
S
Richman
Douglas
D
Hecht
Frederick M
FM
Dolan
Matthew J
MJ
D000483:Alleles; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D019742:Chemokines, CC / Q000235:genetics*; D015331:Cohort Studies; D018628:Gene Dosage; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D011446:Prospective Studies; D019713:Receptors, CCR5 / Q000235:genetics*
C492767:CCL3L1 protein, human; D019742:Chemokines, CC; D006680:HLA Antigens; D019713:Receptors, CCR5