Impaired human immunodeficiency virus type 1 replicative fitness in atypical viremic non-progressor individuals.
BACKGROUND
Progression rates from initial HIV-1 infection to advanced AIDS vary significantly among infected individuals. A distinct subgroup of HIV-1-infected individuals-termed viremic non-progressors (VNP) or controllers-do not seem to progress to AIDS, maintaining high CD4+T cell counts despite high levels of viremia for many years. Several studies have evaluated multiple host factors, including immune activation, trying to elucidate the atypical HIV-1 disease progression in these patients; however, limited work has been done to characterize viral factors in viremic controllers.


METHODS
We analyzed HIV-1 isolates from three VNP individuals and compared the replicative fitness, near full-length HIV-1 genomes and intra-patient HIV-1 genetic diversity with viruses from three typical (TP) and one rapid (RP) progressor individuals.


RESULTS
Viremic non-progressors and typical patients were infected for >10 years (range 10-17 years), with a mean CD4+T-cell count of 472 cells/mm3(442-529) and 400 cells/mm3(126-789), respectively. VNP individuals had a less marked decline in CD4+cells (mean -0.56, range -0.4 to -0.7 CD4+/month) than TP patients (mean -10.3, -8.2 to -13.1 CD4+/month). Interestingly, VNP individuals carried viruses with impaired replicative fitness, compared to HIV-1 isolates from the TP and RP patients (p < 0.05, 95% CI). Although analyses of the near full-length HIV-1 genomes showed no clear patterns of single-nucleotide polymorphisms (SNP) that could explain the decrease in replicative fitness, both the number of SNPs and HIV-1 population diversity correlated inversely with the replication capacity of the viruses (r= -0.956 andr= -0.878,p< 0.01, respectively).


CONCLUSIONS
It is likely that complex multifactorial parameters govern HIV-1 disease progression in each individual, starting with the infecting virus (phenotype, load, and quasispecies diversity) and the intrinsic ability of the host to respond to the infection. Here we analyzed a subset of viremic controller patients and demonstrated that similar to the phenomenon observed in patients with a discordant response to antiretroviral therapy (i.e., high CD4+cell counts with detectable plasma HIV-1 RNA load), reduced viral replicative fitness seems to be linked to slow disease progression in these antiretroviral-naïve individuals.
0000 0001 1015 3316grid.418095.1Institute of Organic Chemistry and Biochemistry v.v.i., Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
Jan
J
Weber
0000 0000 9149 4843grid.443867.aUniversity Hospital Translational Laboratory, University Hospitals Cleveland Medical Center, Cleveland, OH USA.
Richard M
RM
Gibson
0000 0001 1015 3316grid.418095.1Institute of Organic Chemistry and Biochemistry v.v.i., Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
Lenka
L
Sácká
0000 0001 1015 3316grid.418095.1Institute of Organic Chemistry and Biochemistry v.v.i., Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
Dmytro
D
Strunin
0000 0001 1015 3316grid.418095.1Institute of Organic Chemistry and Biochemistry v.v.i., Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
Jan
J
Hodek
0000 0001 1015 3316grid.418095.1Institute of Organic Chemistry and Biochemistry v.v.i., Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
Jitka
J
Weberová
0000 0001 1015 3316grid.418095.1Institute of Organic Chemistry and Biochemistry v.v.i., Academy of Sciences of the Czech Republic, Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
Marcela
M
Pávová
0000 0000 9149 4843grid.443867.aUniversity Hospital Translational Laboratory, University Hospitals Cleveland Medical Center, Cleveland, OH USA.
David J
DJ
Alouani
0000 0001 2164 3847grid.67105.35Department of Medicine, Case Western Reserve University/University Hospitals Cleveland Medical Center, 10900 Euclid Avenue, Cleveland, OH 44106-7288 USA.
Robert
R
Asaad
0000 0001 2164 3847grid.67105.35Department of Medicine, Case Western Reserve University/University Hospitals Cleveland Medical Center, 10900 Euclid Avenue, Cleveland, OH 44106-7288 USA.
Benigno
B
Rodriguez
0000 0001 2164 3847grid.67105.35Department of Medicine, Case Western Reserve University/University Hospitals Cleveland Medical Center, 10900 Euclid Avenue, Cleveland, OH 44106-7288 USA.
Michael M
MM
Lederman
0000 0000 9149 4843grid.443867.aUniversity Hospital Translational Laboratory, University Hospitals Cleveland Medical Center, Cleveland, OH USA ; 0000 0001 2164 3847grid.67105.35Department of Medicine, Case Western Reserve University/University Hospitals Cleveland Medical Center, 10900 Euclid Avenue, Cleveland, OH 44106-7288 USA ; 0000 0001 2164 3847grid.67105.35Department of Pathology, Case Western Reserve University, Cleveland, OH USA.
Miguel E
0000-0001-9170-5601
ME
Quiñones-Mateu
D000328:Adult; D015331:Cohort Studies; D056084:Genetic Fitness; D014644:Genetic Variation; D016679:Genome, Viral; D015658:HIV Infections / Q000821:virology*; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000302:isolation & purification* / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017422:Sequence Analysis, DNA; D014779:Virus Replication
Disease progression; HIV-1; Replicative fitness; Viremic non-progressors