Adaptation to promiscuous usage of CC and CXC-chemokine coreceptors in vivo correlates with HIV-1 disease progression.
OBJECTIVE
To study coreceptor usage of sequential primary HIV-1 isolates in a longitudinal follow-up cohort of HIV-1-infected men to understand its contribution to pathogenesis of HIV disease.


METHODS
Viral coreceptor usage of sequential primary isolates from HIV-1-infected individuals was examined at various timepoints and data was compared with CD4 cell counts, rates of disease progression and beta-chemokine production.


METHODS
Fifty-eight sequential primary isolates were obtained from four rapid progressors, six late progressors, and three long-term nonprogressors (LTNP) and their coreceptor usage was examined by infection of peripheral blood mononuclear cells (PBMC) from donors with wild-type or non-functional CC-chemokine receptor (CCR)-5, and by infection of GHOST4 cells expressing CD4 and various chemokine receptors [CCR-1-CCR-5, CXC-chemokine receptor (CXCR)-4, BOB/GPR15, BONZO/STRL33]. Production of RANTES and macrophage inflammatory protein (MIP)-1beta was examined using unstimulated or phytohemagglutinin (PHA)-stimulated PBMC isolated from these individuals at multiple timepoints during infection.


RESULTS
A switch from single CCR-5 coreceptor usage to multiple coreceptor usage occurred in all four rapid progressors and three out of six late progressors. In addition to the commonly used coreceptors CXCR-4, CCR-5, and CCR-3, some of the viruses isolated from patients in the terminal stage of infection also used CCR-1, CCR-2b, CCR-4, and BOB as coreceptors. The emergence of viral variants capable of utilizing multiple coreceptors generally preceded CD4 cell decline to < 200 x 10(6)/l and correlated with the onset of AIDS. In contrast, three LTNP maintained exclusive usage of CCR-5 over a period of 7-12 years post-infection. Endogenous production of RANTES and MIP-1beta by PBMC from LTNP was not significantly different from rapid and late progressors. However, PHA-driven production of both chemokines was significantly higher in LTNP, suggesting that in vivo activating stimuli might curtail HIV replication by inducing these chemokines.


CONCLUSIONS
Viral variants capable of utilizing a broad range of coreceptors correlated with HIV-1 disease progression. In contrast, LTNP maintain exclusive usage of CCR-5 and produce higher levels of beta-chemokines. Thus, both viral and host determinants leading to the emergence of viral variants capable of using an expanded range of coreceptors may be likely determinants of disease progression.
HIV/Retrovirus Diseases Branch, Division of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Public Health Services, US Department of Health and Human Serv.
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L
Xiao
D L
DL
Rudolph
S M
SM
Owen
T J
TJ
Spira
R B
RB
Lal
D000222:Adaptation, Physiological; D002460:Cell Line; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism; D015331:Cohort Studies; D018450:Disease Progression; D019204:GTP-Binding Proteins / Q000378:metabolism; D006679:HIV Seropositivity / Q000821:virology*; D015497:HIV-1 / Q000378:metabolism / Q000472:pathogenicity*; D018451:Homosexuality, Male; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008297:Male; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D054397:Receptors, CCR3; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D015728:Receptors, HIV / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism
C515300:CCR1 protein, human; C515334:CCR2 protein, human; C515350:CCR3 protein, human; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; C103539:GPR15 protein, human; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D043562:Receptors, G-Protein-Coupled; D015728:Receptors, HIV; D018000:Receptors, Peptide; D019204:GTP-Binding Proteins