Highly divergent patterns of genetic diversity and evolution in proviral quasispecies from HIV controllers

Abstract

BackgroundOngoing intra-host HIV-1 evolution has been shown in individuals that naturally suppress the viremia to low levels (HIV controllers) by the analysis of the RNA in plasma compartment. Detection of evolution at the DNA proviral compartment in HIV controllers, however, has been more challenging and the precise correlation between the systemic viral suppression level and rate of reservoir’s reseeding in those individuals is not fully understood. In this sense, we examined the proviral DNA quasispecies by single genome amplification of the env gene in a cohort of 23 HIV controllers from Brazil, divided in three groups, according to the level of systemic viral suppression: (1) elite controllers with persistent undetectable viral load (PEC, n = 6); (2) elite controllers with occasional episodes of transient (51–400 copies/mL) viremia (EEC, n = 7); and (3) viremic controllers with persistent low-level (80–2000 copies/mL) viremia (VC, n = 10).ResultsThe HIV-1 diversity of the PBMC-associated proviral quasispecies in EC was significantly (P < 0.01) lower than in VC, but not significantly different between PEC and EEC groups. We detected a considerable variation in the average pairwise nucleotide distance and proportion of unique sequences in the HIV-1 proviral quasispecies of PEC and EEC. Some PEC and EEC displayed highly homogenous proviral populations with large clusters of identical sequences, while others exhibited relatively diverse proviral populations with a high proportion of unique sequences comparable to VC subjects. The long-term (10–15 years) follow-up of the HIV-1 proviral populations revealed a complete evolutionary stasis in one PEC and measurable divergence rates in one EEC [3.1 (1.2–5.6) × 10−3 substitutions/site/year and one VC [2.9 (0.7–5.1) × 10−3 substitutions/site/year].ConclusionsThere is no simple relationship between systemic viral suppression and intra-host proviral diversity or rate of reservoir’s reseeding in chronically infected HIV controllers. Our results demonstrate that very divergent patterns of intra-host viral diversity and divergence could be detected in the setting of natural suppression of HIV-1 replication and that ongoing evolution and reseeding of the PBMC proviral reservoir occurs in some elite controllers.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-017-0354-5) contains supplementary material, which is available to authorized users.

Characterization of HIV-1 Near Full-Length Proviral Genome Quasispecies from Patients with Undetectable Viral Load Undergoing First-Line HAART Therapy

“…Prediction of coreceptor usage showed that most individuals (17/22; 77%) presented only R5-tropic viruses, while five individuals presented X4/R5X4-tropic viruses. The prevalence of R5-tropic viruses was similar to the 78% prevalence found by de Azevedo et al [ 114 ] in another Brazilian cohort.…”

Next-generation sequencing analyses of the emergence and maintenance of mutations in CTL epitopes in HIV controllers with differential viremia control

“…A higher median of divergence was observed for nef (0.6% per year), suggesting that nef has a greater potential for viral diversity than does gag, in agreement with previous studies showing greater conservation of gag [ 71 , 72 ]. Previous observations from our group of lower quasispecies diversity for the env gene from EC samples in comparison to VCs [ 73 ] and the low, but similar, median values of divergence in gag and nef for viral samples from ECs and VCs in the present study indicate that lower levels of viral replication restrict evolution.…”

“…Although most HICs have plasma viral loads below the limit of detection of commercial assays, basal viral replication levels can be detected by ultrasensitive methods [ 59 , 67 , 68 ] and should favor viral evolution to some degree due to the characteristic high-genetic variability from HIV. Several studies have reported lower levels of viral diversity in HICs compared with the levels in typical progressors [ 28 , 29 , 32 , 59 , 69 ]. Gijsberg et al estimated divergence rates of 0.9–1.9% over ten months for gag in HIV-1 samples from typical progressors [ 70 ].…”

Transcriptomics and Targeted Proteomics Analysis to Gain Insights Into the Immune-control Mechanisms of HIV-1 Infected Elite Controllers

“…We speculate that these gender-specific differences are one of the determining factors for whether an individual becomes EC or not. Indeed, the proportion of females within EC is higher compared to other groups of HIV-infected individuals ( Crowell et al, 2015 , de Azevedo et al, 2017 ). Despite extensive data on the male and female difference on disease outcome, research does not sufficiently take gender into account.…”