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

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

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. 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. 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/mm(3) (442-529) and 400 cells/mm(3) (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). 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.