Disease Progression in HIV-1-Infected Viremic Controllers.
BACKGROUND
The mechanism of CD4 T-cell decline in HIV-1 infection is unclear, but the association with plasma viral RNA load suggests viral replication is involved. Indeed, viremic controller patients with low viral RNA loads typically maintain high CD4 T-cell counts. Within a local cohort of 86 viremic controllers, we identify a subgroup (18 "discord controllers") with low CD4 T-cell counts that present clinical uncertainty. The underlying mechanism accounting for CD4 T-cell decline in the face of low or undetectable plasma (RNA) viral load remains unresolved. The objective of this study was to investigate the viral and host immune system dynamics in discord controllers by measuring cellular HIV-1 DNA load, T-cell populations, and T-cell activation markers.


METHODS
We compared discord controllers (viral RNA load <2000 copies/mL, <450 CD4 T-cells/mm) with typical controllers (viral RNA load <2000 copies/mL, >450 CD4 T-cells/mm) and progressors (viral RNA load >10,000 copies/mL, <450 CD4 T-cells/mm). We quantified CD4/CD8 naive/central memory/effector memory subsets (CD45RA/RO ± CD62L), activation levels (CD38HLA-DR), and HIV-1 DNA load.


RESULTS
Discord controllers resembled progressors showing high viral DNA load, depletion of naive CD4 T-cells, and higher activation in all CD4 T-cell subsets, compared with typical controllers. They were similar to typical controllers with lower CD8 T-cell activation compared with progressors.


CONCLUSIONS
Our data are consistent with a relationship between CD4 T-cell activation and disease progression. HIV-1 DNA load may be a better marker of viral replication and disease progression than viral RNA load. Lower level CD8 T-cell activation correlates with low viral RNA load but not with disease progression or viral DNA load.
Centre for Immunology and Infectious Disease, Blizard Institute, Queen Mary University of London.
Katherine C
KC
Groves
David F
DF
Bibby
Duncan A
DA
Clark
Are
A
Isaksen
Jane R
JR
Deayton
Jane
J
Anderson
Chloe
C
Orkin
Andrew J
AJ
Stagg
Aine
A
McKnight
D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis; D000328:Adult; D018791:CD4 Lymphocyte Count; D004279:DNA, Viral / Q000097:blood; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology* / Q000302:isolation & purification*; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology; D019562:Viral Load
D004279:DNA, Viral; D006684:HLA-DR Antigens; D008562:Membrane Glycoproteins; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1