Rate and predictors of progression in elite and viremic HIV-1 controllers

León, Agathe; Pérez, Ignacio Plaza; Ruiz‐Mateos, Ezequiel; Benito, José M.; Leal, Manuel; López-Galı́ndez, Cecilio; Rallón, Norma; Alcamı́, José; López‐Aldeguer, José; Viciana, Pompeyo; Rodrı́guez, Carmen; Grau, Eulàlia; Iribarren, José Antonio; Gatell, José M.; García, Felipe

doi:10.1097/qad.0000000000001050

Cited by 72 publications

(97 citation statements)

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“…The three VNP individuals described in this study had been infected with HIV-1 for at least 10 years at the time the blood sample was taken, with stable CD4 + T-cell counts and high plasma HIV RNA loads. When compared with three typical (TP) and one rapid progressor (RP) patients, the number of CD4 + T-cells barely declined in the VNPs over this period of time, similar to what have been described for other adult and children VNPs [43, 82–84, 86]. No other significant differences were observed among the VNP and TP patients, including plasma viral load levels and basic virus characteristics such as HIV-1 subtype (all clade B) and coreceptor tropism (all CCR5-tropic viruses).…”

Section: Discussionsupporting

confidence: 75%

“…The common (“normal”) inverse correlation between CD4 + T-cell count and plasma HIV RNA load usually governs HIV-1 pathogenesis, i.e., elevated plasma viremia is typically accompanied by a decrease in CD4 + T-cells, leading to disease progression [2]. Some HIV-infected individuals have shown uncommon rates of disease progression (slow, non-progressor or elite controllers) but all of them have reduced or undetected plasma HIV RNA loads [3, 4, 42, 82]. On the other hand, a rare group of patients termed viremic non-progressors (VNP) seem to resemble Simian Immunodeficiency Virus (SIV) infection in sooty mangabeys, i.e., active viral replication without (or very limited) disease progression [26, 82–84].…”

Section: Discussionmentioning

confidence: 99%

“…Some HIV-infected individuals have shown uncommon rates of disease progression (slow, non-progressor or elite controllers) but all of them have reduced or undetected plasma HIV RNA loads [3, 4, 42, 82]. On the other hand, a rare group of patients termed viremic non-progressors (VNP) seem to resemble Simian Immunodeficiency Virus (SIV) infection in sooty mangabeys, i.e., active viral replication without (or very limited) disease progression [26, 82–84]. Here we identified three atypically VNP HIV-infected individuals and proceeded to study their HIV-1 isolates, focusing on replicative fitness and viral genomic analysis to try to understand the maintenance of stable CD4 + T-cell counts despite persistence viremia for more than 10 years, in the absence of antiretroviral treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Although prevalence of elite controllers seems to be less than 1% of the HIV-infected population [96, 97], a recent study involving over 13,000 HIV-infected individuals identified 271 viremic controllers for a 2.03% prevalence [82]. Interestingly, viremic pediatric nonprogressor patients with high CD4 + T cell counts seem to be more common than adults VNP individuals [86].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12981-017-0144-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…5B]) did not change significantly over time. While ECs have on occasion been reported to become viremic, requiring therapy (23)(24)(25), our patients maintained CTL control. Thus, loss of CTL does not explain the increase in integrated HIV DNA in our cohort.…”

Section: Resultsmentioning

confidence: 59%

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Pinzone

Graf

Lynch

et al. 2016

J Virol

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The dynamics of HIV reservoir accumulation off antiretroviral therapy (ART) is underexplored. Levels of integrated HIV DNA in peripheral blood mononuclear cells (PBMCs) were longitudinally monitored before and after antiviral therapy. HIV integration increased over time in both elite controllers (ECs; n ‫؍‬ 8) and noncontrollers (NCs; n ‫؍‬ 6) before ART, whereas integration remained stable in patients on ART (n ‫؍‬ 4). The median annual fold change was higher in NCs than in ECs and negatively correlated with CD4/CD8 T-cell ratio. Cytotoxic T lymphocyte (CTL) function as assessed by infected CD4 T-cell elimination (ICE) and granzyme B activity did not significantly change over time in ECs, suggesting that the gradual increase in integrated HIV DNA observed in ECs was not a result of progressive loss of immune-mediated control. Also, acutely infected (n ‫؍‬ 7) but not chronically infected (n ‫؍‬ 6) patients exhibited a significant drop in integrated HIV DNA 12 months after ART initiation. In conclusion, in the absence of ART, integrated HIV accumulates over time both in NCs and in ECs, at variable individual rates. Starting ART early in infection leads to a greater drop in integrated HIV DNA than does initiating treatment after years of infection. The increase in integrated HIV DNA over time suggests that early treatment may be of benefit in limiting HIV reservoirs. IMPORTANCEThe establishment of a latent reservoir represents a barrier to cure among HIV-infected individuals. The dynamics of HIV reservoir accumulation over time in patients before antiviral therapy is underexplored, in large part because it is difficult to accurately and reproducibly measure the size of HIV reservoir in this setting. In our study, we compared the dynamics of integrated HIV DNA over time in ECs and NCs before and after ART was initiated. We found that integrated HIV DNA levels progressively increase over time in the absence of ART, but with a higher, albeit variable, rate in NCs compared to ECs. In addition, integrated HIV DNA declines more dramatically when ART is initiated in acute rather than chronic HIV infection, suggesting important differences between acute and chronic infection. Our study highlights the role of HIV replication and CTL control in reservoir accumulation in sanctuary sites and why ART appears to be more effective in acute infection.

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Dynamics in HIV‐DNA levels over time in HIV controllers

et al. 2019

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Introduction HIV controllers (HIC) maintain viraemia at low levels without antiretroviral treatment and have small HIV reservoirs. Nevertheless, they are heterogeneous regarding their risk of infection progression. The study of reservoirs can help elucidate this control. This study aimed to explore the factors implicated in the pathogenesis of HIV infection that are potentially associated with HIV reservoirs and their dynamics in HIC.MethodsIndividuals living with HIV included in the ANRS‐CODEX cohort with at least two HIV‐DNA measurements between 2009 and 2016 were selected. The total HIV‐DNA levels had been quantified prospectively from blood samples. Mixed‐effect linear models estimated the HIV‐DNA dynamics over time.ResultsThe median (interquartile range (IQR)) HIV‐DNA level was 1.5 (1.3 to 1.9) log copies/million peripheral blood mononuclear cells at inclusion (n = 202 individuals). These low levels showed heterogeneity among HIC. Lower levels were then associated with the protective HLA‐B*27/B*57 alleles and/or lower HIV‐RNA level at inclusion, negative hepatitis C virus serology, lower HIV‐suppressive capacity of specific CD8 T cells and lower levels of immune activation and inflammation. Interestingly, mathematical modelling of the dynamics of HIV‐DNA over time (840 measurements) showed that the number of infected cells decreased in 46% of HIC (follow‐up: 47.6 months) and increased in 54% of HIC. A multivariate analysis indicated that HLA‐B*27/B*57 alleles, a low level of HIV‐RNA and a low level of HIV‐DNA at inclusion were markers independently associated with this decrease.ConclusionsThese results offer new insights into the mechanisms of long‐term control in HIC. In half of HIC, the decrease in HIV‐DNA level could be linked to tighter viral control and progressive loss of infected cells. These findings allow the identification of HIC with a low risk of progression who may not need treatment.

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Rate and predictors of progression in elite and viremic HIV-1 controllers

Abstract: HIV-1 disease progression in elite and viremic controllers is frequent. We propose a baseline clinical score to easily classify these patients according to risk of progression. This score could be instrumental for taking clinical decisions and performing pathogenic studies.

Cited by 72 publications

References 40 publications

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

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

Monitoring Integration over Time Supports a Role for Cytotoxic T Lymphocytes and Ongoing Replication as Determinants of Reservoir Size

Dynamics in HIV‐DNA levels over time in HIV controllers

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