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. 2017 Jul 15;216(2):254-262.
doi: 10.1093/infdis/jix265.

Human Immunodeficiency Virus Type 1 Persistence Following Systemic Chemotherapy for Malignancy

Timothy J Henrich  1   2   3 , Kristen S Hobbs  1   2 , Emily Hanhauser  1   2 , Eileen Scully  2   3   4 , Louise E Hogan  1   2   3 , Yvonne P Robles  2 , Kaitlyn S Leadabrand  1 , Francisco M Marty  2   3   4 , Christine D Palmer  5 , Stephanie Jost  5   6 , Christian Körner  5 , Jonathan Z Li  2   3 , Rajesh T Gandhi  3   5   7 , Ayad Hamdan  3   6 , Jeremy Abramson  3   7 , Ann S LaCasce  3   4 , Daniel R Kuritzkes  2   3
Affiliations

Human Immunodeficiency Virus Type 1 Persistence Following Systemic Chemotherapy for Malignancy

Timothy J Henrich et al. J Infect Dis. .

Abstract

Background: Systemic chemotherapies for various malignancies have been shown to significantly, yet transiently, decrease numbers of CD4+ T lymphocytes, a major reservoir for human immunodeficiency virus type 1 (HIV-1) infection. However, little is known about the impact of cytoreductive chemotherapy on HIV-1 reservoir dynamics, persistence, and immune responses.

Methods: We investigated the changes in peripheral CD4+ T-cell-associated HIV-1 DNA and RNA levels, lymphocyte activation, viral population structure, and virus-specific immune responses in a longitudinal cohort of 15 HIV-1-infected individuals receiving systemic chemotherapy or subsequent autologous stem cell transplantation for treatment of hematological malignancies and solid tumors.

Results: Despite a transient reduction in CD4+ T cells capable of harboring HIV-1, a 1.7- and 3.3-fold increase in mean CD4+ T-cell-associated HIV-1 RNA and DNA, respectively, were observed months following completion of chemotherapy in individuals on antiretroviral therapy. We also observed changes in CD4+ T-cell population diversity and clonal viral sequence expansion during CD4+ T-cell reconstitution following chemotherapy cessation. Finally, HIV-1 DNA was preferentially, and in some cases exclusively, detected in cytomegalovirus (CMV)- and Epstein-Barr virus (EBV)-responsive CD4+ T cells following chemotherapy.

Conclusions: Expansion of HIV-infected CMV/EBV-specific CD4 + T cells may contribute to maintenance of the HIV DNA reservoir following chemotherapy.

Keywords: HIV-1; chemotherapy; cytomegalovirus infection; lymphoma; stem cell transplantation.

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Figures

Figure 1.
Figure 1.
CD4+ T cell–associated human immunodeficiency virus (HIV) DNA and RNA levels prior to and following completion of chemotherapy for hematologic malignancies and Kaposi sarcoma. Significant increases in both HIV DNA (A) and HIV RNA (C) in paired analyses were observed following completion of chemotherapy (postchemotherapy time points) compared with prechemotherapy or the first sampling time point while receiving cancer treatment (n = 10). Statistical significance was lost if only prechemotherapy time points are compared with those after completion of therapy for both DNA (B) and RNA (D), but paired sample size was smaller (n = 7), and up to a 1 log increase in DNA levels was still observed. Bars represent mean values and standard error. Paired, nonparametric Wilcoxon tests were used.
Figure 2.
Figure 2.
Mean percentages of intracellular Ki67 expression and surface expression of CD38, HLA-DR, and CD57 on CD4+ and CD8+ T cells prior and following completion of chemotherapy in participants with lymphoma or Kaposi sarcoma. Nonsignificant decreases in T-cell activation (CD38+ HLA-DR+ dual positive) and proliferation (Ki67+) were observed by the second postchemotherapy sampling time point. Bars represent mean values and standard error.
Figure 3.
Figure 3.
Maximum likelihood phylogenetic trees of single-genome human immunodeficiency virus type 1 (HIV-1) envelope DNA sequences from pre- or on-chemotherapy and postchemotherapy CD4+ T cells in patients with lymphoma on stable antiretroviral therapy throughout chemotherapy. Oligoclonal clustering of sequences was observed only following completion of chemotherapy in participants 4 and 6, with an increase in the number of near-identical envelope sequences following chemotherapy in participant 7. Phylogenetic trees were generated using bootstrapped, generalized time-reversible models. Bars represent genetic distance. Mean genetic distances for each participant time point are as follows: participant 2 prechemotherapy D = 0.019, postchemotherapy D = 0.032; participant 4 prechemotherapy D = 0.015, first postchemotherapy D = 0.032, second postchemotherapy D = 0.012; participant 6 prechemotherapy D = 0.018, postchemotherapy D = 0.019; participant 7 first on-chemotherapy D = 0.046, postchemotherapy D = 0.033. When excluding the single postchemotherapy outlier sequence from participant 6, the prechemotherapy D = 0.024 and postchemotherapy D = 0.013.
Figure 4.
Figure 4.
Functional CD4+ T-cell responses to Epstein-Barr virus (EBV)/cytomegalovirus (CMV) lysate stimulation and CD4+ T cell–associated human immunodeficiency virus (HIV) DNA levels within responsive and unresponsive cells. CD4+ T cells were exposed to CMV/EBV lysates followed by fluorescence-activated cell sorting and enumeration of cells that produced interleukin 2 (IL-2) and/or interferon gamma (IFN-γ) (A). HIV DNA extracted and enumerated by quantitative polymerase chain reaction (qPCR) was found to be highest in cells responding to CMV/EBV antigen despite these cells being the least frequent (B).
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