A combination of defective DNA and protective host factors are found in a set of HIV-1 ancestral LTNPs

Sandonís, Virginia; Casado, Concepción; Alvaro, Tamara; Pernas, María; Olivares, Isabel; Garcı́a, Soledad; Rodrı́guez, Carmen; Romero, Jorge del; López-Galı́ndez, Cecilio

doi:10.1016/j.virol.2009.05.022

Cited by 29 publications

(38 citation statements)

References 41 publications

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“…In TP with RNA viral loads above 10,000 copies/mL, env gene diversity increases at a mean rate of 1%/year and reaches a peak (π = 6–10%) after 5–10 years post-infection [3]. High levels of env proviral diversity (π = 4-8%) have been also described in samples taken 10–15 years after HIV diagnosis from LTNPs with plasma viremia between 2000 and 10,000 copies/mL [4, 16, 17, 19, 45]. Much lower levels of env proviral diversity (π = 0.1–6%), by contrast, were detected here in samples taken between 5 and 20 years after HIV diagnosis from HIV controllers (RNA viral load lower than 2000 copies/mL).…”

Section: Discussionmentioning

confidence: 99%

“…In some LTNPs, DNA proviral populations are composed of a complex mixture of archival (dating close to the patient’s seroconversion time) and recent (dating close to the sampling time) variants [13] and displayed no temporal structure in the changes of diversity and divergence during chronic infection [14]. In all chronically infected EC and some VC, DNA proviral populations are extremely homogenous (with less than 2% env diversity), mostly composed by ancestral sequences and with no measurable divergence over time [5, 9, 10, 12, 15–19]. A recent study demonstrates that most proviral sequences detected in PBMC from HIV controllers are largely representative of archival variants probably integrated during primary infection and propagated by clonal expansion of the memory CD4 + T cell latent reservoir, although rare proviral clones of recent origin could be detected in some patients [12].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…Some studies have shown that virus strains from LTNPs are less evolved and thus less capable of evading the host immunological response when compared with progressor strains (Sandonís et al, 2009;Wang et al, 2003). The classic example of HIV-1 LTNP virus attenuation is the Sydney Blood Bank cohort (n58), whose members were infected from blood transfusions from the same donor infected with an HIV-1 strain that contained a large Mechanisms of control in HIV-1 LTNPs deletion in a long-terminal repeat from a conserved and biologically significant area in the nef gene (Crotti et al, 2006;Learmont et al, 1999).…”

Section: Ltnp Virus Attenuationmentioning

confidence: 99%

Human immunodeficiency virus type 1 long-term non-progressors: the viral, genetic and immunological basis for disease non-progression

Poropatich

Sullivan

2010

Journal of General Virology

144

119

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“…Analyses of HIV long-term nonprogressors (LTNPs) and elite controllers (ECs) suggest diverse and multifactorial mechanisms of natural control of viremia. Factors contributing to elite control (undetectable HIV viral load) may include attenuated viruses with slow viral evolution (19,20), although replication-defective viruses are by no means always present (21)(22)(23)(24). HLA-B*57-positive elite controllers maintained viral suppression despite the presence of escape mutations, with evidence of CTL responses against unmutated epitopes and de novo responses against epitopes with escape mutations (25)(26)(27).…”

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confidence: 99%

CD8 ⁺ T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles

Koofhethile

Ndhlovu

Thobakgale-Tshabalala

et al. 2016

J Virol

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The mechanisms of viral control and loss of viral control in chronically infected individuals with or without protective HLA class I alleles are not fully understood. We therefore characterized longitudinally the immunological and virological features that may explain divergence in disease outcome in 70 HIV-1 C-clade-infected antiretroviral therapy (ART)-naive South African adults, 35 of whom possessed protective HLA class I alleles. We demonstrate that, over 5 years of longitudinal study, 35% of individuals with protective HLA class I alleles lost viral control compared to none of the individuals without protective HLA class I alleles (P ‫؍‬ 0.06). Sustained HIV-1 control in patients with protective HLA class I alleles was characteristically related to the breadth of HIV-1 CD8 ؉ T cell responses against Gag and enhanced ability of CD8 ؉ T cells to suppress viral replication ex vivo. In some cases, loss of virological control was associated with reduction in the total breadth of CD8 ؉ T cell responses in the absence of differences in HIV-1-specific CD8 ؉ T cell polyfunctionality or proliferation. In contrast, viremic controllers without protective HLA class I alleles possessed reduced breadth of HIV-1-specific CD8 ؉ T cell responses characterized by reduced ability to suppress viral replication ex vivo. These data suggest that the control of HIV-1 in individuals with protective HLA class I alleles may be driven by broad CD8 ؉ T cell responses with potent viral inhibitory capacity while control among individuals without protective HLA class I alleles may be more durable and mediated by CD8 ؉ T cell-independent mechanisms. H IV remains a global problem, and sub-Saharan Africa continues to bear the brunt of the epidemic, accounting for 67% of the infected people worldwide (1). Understanding the mechanisms of natural viral control in HIV infection is crucial for the identification of correlates of immune protection and for the design of an effective HIV vaccine. Previous studies have linked HIV control to a number of immunological factors, particularly HIVspecific CD8 ϩ cytotoxic T lymphocytes (CTLs), which have been demonstrated to play an important role (2-5). However, virusspecific CD8 ϩ T cell immune responses are not equally effective in HIV control, as the majority of infected individuals progress to disease despite the presence of these cells. HIV is able to evade immune responses by developing mutations that mediate escape from CTL recognition (6-12). In addition, the expression of certain HLA class I molecules by HIV-infected patients, such as HLA-B*27, HLA-B*57, HLA-B*58:01, HLA-B*81:01, and HLA-A*74: 01, is associated with better clinical disease outcomes in some population settings (3,(13)(14)(15)(16)(17)(18). HLA class I proteins present viral peptides on the surface of antigen-presenting cells to CTLs, and a major mechanism by which these protective alleles slow HIV disease progression is believed to be through CTL activity (18).

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A combination of defective DNA and protective host factors are found in a set of HIV-1 ancestral LTNPs

Cited by 29 publications

References 41 publications

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

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

Human immunodeficiency virus type 1 long-term non-progressors: the viral, genetic and immunological basis for disease non-progression

CD8 ⁺ T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles

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A combination of defective DNA and protective host factors are found in a set of HIV-1 ancestral LTNPs

Cited by 29 publications

References 41 publications

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

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

Human immunodeficiency virus type 1 long-term non-progressors: the viral, genetic and immunological basis for disease non-progression

CD8 + T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles

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CD8 ⁺ T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles