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Impaired T-cell proliferation among HAART-treated adults with suboptimal CD4 recovery in an African cohort.

Abstract

BACKGROUND

Most HIV-infected subjects exhibit a progressive rise in CD4 T-cell counts after initiation of highly active antiretroviral therapy (HAART). However, a subset of individuals exhibit very poor CD4 T-cell recovery despite effective control of HIV-RNA viraemia. We evaluated CD4 T-cell proliferation among suboptimal responders and its correlation with CD4 T-cell activation.

METHODS

The magnitude of CD4 increase (difference between absolute CD4 counts at baseline and absolute CD4 counts at 4 years of ART) was grouped into 4 quartiles for the 211 patients with sustained HIV-RNA viral suppression. Cases of 'Suboptimal immune responders' included patients within the lowest quartile [Median CD4 increase 165 (Range -43-298) cells/μl; n=52] and a comparison group of 'Optimal immune responders' was defined as patients within the highest quartile of CD4 increase [Median CD4 increase 528 (Range 417-878) cells/μl; n=52]. Frozen PBMC were thawed and analysed from a convenient sample of 39 suboptimal responders and 48 optimal responders after 4 years of suppressive antiretroviral therapy. T-cell activation was measured by proportions of T-cells expressing surface marker CD38 and HLADR (CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ cells). T-cell proliferation was determined by the extent of carboxyfluorescein diacetate succinimidyl ester (CFSE) dye dilution on culture day 5 of PBMCs in the presence of antigen (SEB, PPD, CMVpp65, GagA and GagD). Samples were analyzed on a FACS Calibur flow cytometer and flow data was analyzed using FlowJo and GraphPad.

RESULTS

Overall, CD4 T-cell proliferation on stimulation with SEB, PPD, CMVpp65, Gag A and Gag D.antigens, was lower among suboptimal than optimal responders; this was significant for SEB (CD4+ p=0.003; CD8+ p=0.048) and PPD antigens (CD8+ p=0.038). Among suboptimal responders, T-cell proliferation decreased with increasing immune activation (Negative correlation; slope = -0.13±-0.11) but not among optimal responders.

CONCLUSION

T-cell immune activation and exhaustion were associated with poor proliferation among suboptimal responders to HAART despite sustained viral suppression. We recommend studies to further understand the mechanisms leading to impaired T-cell function among suboptimal responders as well as the potential role of immune modulation in optimizing CD4 count and functional recovery after HAART.

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  • Authors+Show Affiliations

    ,

    Makerere University College of Health Sciences, Kampala, Uganda. drdamalie@yahoo.com

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    Source

    BMC immunology 14: 2013 Jun 20 pg 26

    MeSH

    Adult
    Antigens
    Antiretroviral Therapy, Highly Active
    CD4-Positive T-Lymphocytes
    CD8-Positive T-Lymphocytes
    Cell Proliferation
    Cohort Studies
    Demography
    Female
    Fluoresceins
    HIV Infections
    Humans
    Lymphocyte Activation
    Male
    Succinimides
    Uganda

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    23786370

    Citation

    Nakanjako, Damalie, et al. "Impaired T-cell Proliferation Among HAART-treated Adults With Suboptimal CD4 Recovery in an African Cohort." BMC Immunology, vol. 14, 2013, p. 26.
    Nakanjako D, Ssewanyana I, Nabatanzi R, et al. Impaired T-cell proliferation among HAART-treated adults with suboptimal CD4 recovery in an African cohort. BMC Immunol. 2013;14:26.
    Nakanjako, D., Ssewanyana, I., Nabatanzi, R., Kiragga, A., Kamya, M. R., Cao, H., & Mayanja-Kizza, H. (2013). Impaired T-cell proliferation among HAART-treated adults with suboptimal CD4 recovery in an African cohort. BMC Immunology, 14, p. 26. doi:10.1186/1471-2172-14-26.
    Nakanjako D, et al. Impaired T-cell Proliferation Among HAART-treated Adults With Suboptimal CD4 Recovery in an African Cohort. BMC Immunol. 2013 Jun 20;14:26. PubMed PMID: 23786370.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Impaired T-cell proliferation among HAART-treated adults with suboptimal CD4 recovery in an African cohort. AU - Nakanjako,Damalie, AU - Ssewanyana,Isaac, AU - Nabatanzi,Rose, AU - Kiragga,Agnes, AU - Kamya,Moses R, AU - Cao,Huyen, AU - Mayanja-Kizza,Harriet, Y1 - 2013/06/20/ PY - 2012/12/19/received PY - 2013/06/18/accepted PY - 2013/6/22/entrez PY - 2013/6/22/pubmed PY - 2013/11/15/medline SP - 26 EP - 26 JF - BMC immunology JO - BMC Immunol. VL - 14 N2 - BACKGROUND: Most HIV-infected subjects exhibit a progressive rise in CD4 T-cell counts after initiation of highly active antiretroviral therapy (HAART). However, a subset of individuals exhibit very poor CD4 T-cell recovery despite effective control of HIV-RNA viraemia. We evaluated CD4 T-cell proliferation among suboptimal responders and its correlation with CD4 T-cell activation. METHODS: The magnitude of CD4 increase (difference between absolute CD4 counts at baseline and absolute CD4 counts at 4 years of ART) was grouped into 4 quartiles for the 211 patients with sustained HIV-RNA viral suppression. Cases of 'Suboptimal immune responders' included patients within the lowest quartile [Median CD4 increase 165 (Range -43-298) cells/μl; n=52] and a comparison group of 'Optimal immune responders' was defined as patients within the highest quartile of CD4 increase [Median CD4 increase 528 (Range 417-878) cells/μl; n=52]. Frozen PBMC were thawed and analysed from a convenient sample of 39 suboptimal responders and 48 optimal responders after 4 years of suppressive antiretroviral therapy. T-cell activation was measured by proportions of T-cells expressing surface marker CD38 and HLADR (CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ cells). T-cell proliferation was determined by the extent of carboxyfluorescein diacetate succinimidyl ester (CFSE) dye dilution on culture day 5 of PBMCs in the presence of antigen (SEB, PPD, CMVpp65, GagA and GagD). Samples were analyzed on a FACS Calibur flow cytometer and flow data was analyzed using FlowJo and GraphPad. RESULTS: Overall, CD4 T-cell proliferation on stimulation with SEB, PPD, CMVpp65, Gag A and Gag D.antigens, was lower among suboptimal than optimal responders; this was significant for SEB (CD4+ p=0.003; CD8+ p=0.048) and PPD antigens (CD8+ p=0.038). Among suboptimal responders, T-cell proliferation decreased with increasing immune activation (Negative correlation; slope = -0.13±-0.11) but not among optimal responders. CONCLUSION: T-cell immune activation and exhaustion were associated with poor proliferation among suboptimal responders to HAART despite sustained viral suppression. We recommend studies to further understand the mechanisms leading to impaired T-cell function among suboptimal responders as well as the potential role of immune modulation in optimizing CD4 count and functional recovery after HAART. SN - 1471-2172 UR - https://www.unboundmedicine.com/medline/citation/23786370/Impaired_T_cell_proliferation_among_HAART_treated_adults_with_suboptimal_CD4_recovery_in_an_African_cohort_ L2 - https://bmcimmunol.biomedcentral.com/articles/10.1186/1471-2172-14-26 DB - PRIME DP - Unbound Medicine ER -