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. 2009 Oct 30;4(10):e7658.
doi: 10.1371/journal.pone.0007658.

HIV-1 residual viremia correlates with persistent T-cell activation in poor immunological responders to combination antiretroviral therapy

Maud Mavigner  1 , Pierre Delobel, Michelle Cazabat, Martine Dubois, Fatima-Ezzahra L'faqihi-Olive, Stéphanie Raymond, Christophe Pasquier, Bruno Marchou, Patrice Massip, Jacques Izopet
Affiliations

HIV-1 residual viremia correlates with persistent T-cell activation in poor immunological responders to combination antiretroviral therapy

Maud Mavigner et al. PLoS One. .

Abstract

Background: The clinical significance and cellular sources of residual human immunodeficiency virus type 1 (HIV-1) production despite suppressive combination antiretroviral therapy (cART) remain unclear and the effect of low-level viremia on T-cell homeostasis is still debated.

Methodology/principal findings: We characterized the recently produced residual viruses in the plasma and short-lived blood monocytes of 23 patients with various immunological responses to sustained suppressive cART. We quantified the residual HIV-1 in the plasma below 50 copies/ml, and in the CD14(high) CD16(-) and CD16+ monocyte subsets sorted by flow cytometry, and predicted coreceptor usage by genotyping V3 env sequences. We detected residual viremia in the plasma of 8 of 10 patients with poor CD4+ T-cell reconstitution in response to cART and in only 5 of 13 patients with good CD4+ T-cell reconstitution. CXCR4-using viruses were frequent among the recently produced viruses in the plasma and in the main CD14(high) CD16(-) monocyte subset. Finally, the residual viremia was correlated with persistent CD4+ and CD8+ T-cell activation in patients with poor immune reconstitution.

Conclusions: Low-level viremia could result from the release of archived viruses from cellular reservoirs and/or from ongoing virus replication in some patients. The compartmentalization of the viruses between the plasma and the blood monocytes suggests at least two origins of residual virus production during effective cART. CXCR4-using viruses might be produced preferentially in patients on cART. Our results also suggest that low-level HIV-1 production in some patients may contribute to persistent immune dysfunction despite cART.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. HIV-1 compartmentalization between CD14high CD16− and CD16+ monocytes.
Phylogenetic trees of HIV-1 env sequences obtained by clonal analysis of PCR products from CD14high CD16− monocytes (open squares), CD16+ monocytes (open diamonds), and CD4+ T-cells (open circles). Blue symbols represent sequences that predict CCR5 coreceptor use; red symbols represent sequences that predict CXCR4 coreceptor use. The bar indicates genetic distance. Bootstrap values are expressed as percentages for each relevant node and represent the percentage occurrence of that node calculated using 100 bootstrap replicates. (A) Phylogenetic tree of HIV-1 env sequences of patient 18 (B) Phylogenetic tree of HIV-1 env sequences of patient 29.
Figure 2
Figure 2. Residual HIV-1 RNA in the plasma.
Comparison of the level of residual HIV-1 RNA in the plasma of the poor (n = 10) and good immunological responders to cART (n = 13).
Figure 3
Figure 3. Difference between plasma and CD4+ T-cells viruses during cART and plasma viruses at baseline.
Phylogenetic trees of HIV-1 env sequences obtained by clonal analysis of PCR products from CD4+ T-cells (open circles), plasma on cART (open triangles) and plasma at baseline (closed triangles). Blue symbols represent sequences that predict CCR5 coreceptor use; red symbols represent sequences that predict CXCR4 coreceptor use. The bar indicates genetic distance. Bootstrap values are expressed as percentages for each relevant node and represent the percentage occurrence of that node calculated using 100 bootstrap replicates. (A) Phylogenetic tree of HIV-1 env sequences of patient 2 (B) Phylogenetic tree of HIV-1 env sequences of patient 3.
Figure 4
Figure 4. Genetic evolution of HIV-1 despite effective cART.
Phylogenetic trees of HIV-1 env sequences obtained from CD14high CD16− monocytes (open squares), CD4+ T-cells (open circles), and plasma (open triangles) during cART, and plasma (closed triangles) and PBMCs (closed stars) at baseline before starting cART. Blue symbols represent sequences that predict CCR5 coreceptor use; red symbols represent sequences that predict CXCR4 coreceptor use. The bar indicates genetic distance. Bootstrap values are expressed as percentages for each relevant node and represent the percentage occurrence of that node calculated using 100 bootstrap replicates. (A) Phylogenetic tree of HIV-1 env sequences of patient 16 (B) Phylogenetic tree of HIV-1 env sequences of patient 15.
Figure 5
Figure 5. Correlation between residual viremia and immunological parameters of CD4+ T-cell homeostasis.
(A) Correlation between the residual plasma virus concentration and the frequency of sjTREC-bearing cells in the CD31+ subset of naïve CD4+ T-cells; (B) Correlation between the residual plasma virus concentration and the absolute numbers of CD31high naïve CD4+ T-cells per mm3 of blood; (C and D) Correlation between the residual plasma virus concentration and CD4+ T-cell activation in the poor and good immunological responders.
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References

    1. Bailey JR, Sedaghat AR, Kieffer T, Brennan T, Lee PK, et al. Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells. J Virol. 2006;80:6441–6457. - PMC - PubMed
    1. Dornadula G, Zhang H, VanUitert B, Stern J, Livornese L, Jr, et al. Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. Jama. 1999;282:1627–1632. - PubMed
    1. Havlir DV, Strain MC, Clerici M, Ignacio C, Trabattoni D, et al. Productive infection maintains a dynamic steady state of residual viremia in human immunodeficiency virus type 1-infected persons treated with suppressive antiretroviral therapy for five years. J Virol. 2003;77:11212–11219. - PMC - PubMed
    1. Maldarelli F, Palmer S, King MS, Wiegand A, Polis MA, et al. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog. 2007;3:e46. - PMC - PubMed
    1. Palmer S, Maldarelli F, Wiegand A, Bernstein B, Hanna GJ, et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A. 2008;105:3879–3884. - PMC - PubMed

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