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01.12.2017 | Research | Ausgabe 1/2017 Open Access

AIDS Research and Therapy 1/2017

Impaired human immunodeficiency virus type 1 replicative fitness in atypical viremic non-progressor individuals

Zeitschrift:
AIDS Research and Therapy > Ausgabe 1/2017
Autoren:
Jan Weber, Richard M. Gibson, Lenka Sácká, Dmytro Strunin, Jan Hodek, Jitka Weberová, Marcela Pávová, David J. Alouani, Robert Asaad, Benigno Rodriguez, Michael M. Lederman, Miguel E. Quiñones-Mateu
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s12981-017-0144-0) contains supplementary material, which is available to authorized users.

Abstract

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 and r = −0.878, p < 0.01, respectively).

Conclusion

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.
Zusatzmaterial
Additional file 1: Figure S1. CD4 + T-cell counts and plasma HIV-1 RNA load values available for all seven patients described in this study. Vertical dashed lines indicate the time of sampling. Grey arrows depict the number of years since primary HIV-1 infection. The period of time the patients were under antiretroviral treatment (ART) is indicated by black boxes.
Additional file 2: Figure S2. Subtyping of the near full-length HIV-1 consensus sequences, obtained by deep sequencing, was performed using the Recombination Identification Program (RIP 3.0) from the Los Alamos HIV Sequence Database as described (1). The similarity plots show distance measurements between the query sequence (patient-derived HIV-1) and the reference HIV-1 sequences from different subtypes.
Additional file 3: Figure S3. Hierarchical clustering analysis of single nucleotide polymorphisms (SNPs) in all HIV-1 coding regions plus the long-terminal regions (LTRs). Dendograms were calculated using the Euclidian distance and Complete cluster methods with 1000 bootstrap iterations as described in Los Alamos HIV Sequence Database ( https://​www.​hiv.​lanl.​gov.​content/​sequence/​HEATMAP/​heatmap.​html). Bootstrap values >60% are indicated by an asterisk. Green and grey blocks indicate the presence and absence of SNPs, respectively.
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