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Therapeutic Immune Recovery and Reduction of CXCR4-Tropic HIV-1


Bader, J; Däumer, M; Schöni-Affolter, F; Böni, J; Gorgievski-Hrisoho, Meri; Martinetti, G; Thielen, A; Klimkait, T (2016). Therapeutic Immune Recovery and Reduction of CXCR4-Tropic HIV-1. Clinical Infectious Diseases, 64(3):295-300.

Abstract

Background. In the absence of therapy, CXCR4 (X4)–tropic human immunodeficiency virus type 1 (HIV-1) increases over time, associated with accelerated disease progression. In contrast, the majority of patients receiving long-term combination antiretroviral therapy (cART) present with CCR5 (R5)-tropic HIV-1 variants. It is unclear whether cART itself mediates the reduction of X4-tropic HIV-1. The current study aimed at assessing the tropism of viral integrates in patients’ blood during fully suppressive cART. Methods. The relative frequencies of X4-tropic proviral HIV-1 variants were determined by means of next-generation sequencing (False Positive Rate (FPR), 3.5%; R5- or X4 tropic variants occurring at less than 2% of the total virus population) for 35 treated patients in the Swiss HIV Cohort Study and followed longitudinally over time. Full viral suppression and a continuous CD4 T-cell recovery during cART were documented for all patients. Viral phylogenetic changes and sequence evolution were analyzed. Results. The majority of patients (80%) experienced no frequency increase in X4-tropic proviruses during therapy. Although some proviral sequence evolution was demonstrable in >50% of these patients during therapy, this growing viral diversity was in no case paralleled by the emergence or expansion of X4-tropic provirus variants. In the remaining 20% of patients, the documented expansion of X4-tropic provirus was based on the outgrowth of single viral variants from minority populations already present before therapy initiation. Conclusion. Our study demonstrates that X4-tropic HIV sharply declines in most patients during successful therapy, which indicates a preferential tropism-dependent provirus elimination in the immunocompetent host. The recently implemented World Health Organization strategies of immediate therapy initiation are fully in line with this gradual loss of X4 tropism during therapy. Moreover, the early use of coreceptor antagonists against the remaining CCR5-tropic viruses may be indicated.

Abstract

Background. In the absence of therapy, CXCR4 (X4)–tropic human immunodeficiency virus type 1 (HIV-1) increases over time, associated with accelerated disease progression. In contrast, the majority of patients receiving long-term combination antiretroviral therapy (cART) present with CCR5 (R5)-tropic HIV-1 variants. It is unclear whether cART itself mediates the reduction of X4-tropic HIV-1. The current study aimed at assessing the tropism of viral integrates in patients’ blood during fully suppressive cART. Methods. The relative frequencies of X4-tropic proviral HIV-1 variants were determined by means of next-generation sequencing (False Positive Rate (FPR), 3.5%; R5- or X4 tropic variants occurring at less than 2% of the total virus population) for 35 treated patients in the Swiss HIV Cohort Study and followed longitudinally over time. Full viral suppression and a continuous CD4 T-cell recovery during cART were documented for all patients. Viral phylogenetic changes and sequence evolution were analyzed. Results. The majority of patients (80%) experienced no frequency increase in X4-tropic proviruses during therapy. Although some proviral sequence evolution was demonstrable in >50% of these patients during therapy, this growing viral diversity was in no case paralleled by the emergence or expansion of X4-tropic provirus variants. In the remaining 20% of patients, the documented expansion of X4-tropic provirus was based on the outgrowth of single viral variants from minority populations already present before therapy initiation. Conclusion. Our study demonstrates that X4-tropic HIV sharply declines in most patients during successful therapy, which indicates a preferential tropism-dependent provirus elimination in the immunocompetent host. The recently implemented World Health Organization strategies of immediate therapy initiation are fully in line with this gradual loss of X4 tropism during therapy. Moreover, the early use of coreceptor antagonists against the remaining CCR5-tropic viruses may be indicated.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Virology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:HIV, tropism, CXCR4-tropic, immune system
Language:English
Date:12 November 2016
Deposited On:26 Jan 2017 08:09
Last Modified:18 Apr 2018 11:48
Publisher:Oxford University Press
ISSN:1058-4838
Funders:Swiss HIV Cohort Study (SHCS), Swiss National Science Foundation (grant 148522), SHCS projects 521 and 739, SHCS research foundation
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/cid/ciw737
PubMed ID:27838645
Project Information:
  • : Funder
  • : Grant ID
  • : Project TitleSwiss HIV Cohort Study (SHCS)
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSwiss National Science Foundation (grant 148522)
  • : Funder
  • : Grant ID
  • : Project TitleSHCS projects 521 and 739
  • : Funder
  • : Grant ID
  • : Project TitleSHCS research foundation

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