Abstract
BackgroundProgression 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.MethodsWe 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.ResultsViremic 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).ConclusionIt 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.
Highlights
Progression rates from initial human immunodeficiency virus type 1 (HIV-1) infection to advanced AIDS vary significantly among infected individu‐ als
Virologic, and immunologic characteristics of viremic non‐progressors, typical and rapid progressor patients As described above, for this study we identified three treatment-naïve HIV-infected individuals classified as viremic non-progressors (VNP)
At the time of the study, these patients were infected with HIV-1 for over 10 years, maintaining relatively high CD4+ T-cell counts with limited decline in CD4+ T-cell count despite sustained plasma HIV-1 RNA loads above 4000 copies/ml during the time these patients were monitored prior to this study (Table 1; Additional file 1: Figure S1)
Summary
Progression rates from initial HIV-1 infection to advanced AIDS vary significantly among infected individu‐ als. Based on plasma HIV-1 RNA (viral) load, CD4+ T-cell counts, and symptomatic or asymptomatic HIV-1 infection adult patients have been classified into four groups: (i) rapid progressors (RP), (ii) typical progressors (TP), and two groups of long-term non-progressors (LTNP) namely (iii) elite controllers and (iv) viremic controllers [3, 4] Among the latter, a rare subgroup of HIV-1-infected individuals has been described who do not seem to progress to AIDS, maintaining high CD4+ T-cell counts despite high levels of viremia (i.e., over 2000 HIV-1 copies RNA/ml of plasma) for many years, called viremic non-progressors (VNPs) [5,6,7,8]. It has been long recognized that immune activation is one of the major contributors to HIV-1 disease and pathogenesis [6, 24,25,26,27]
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