Immune activation correlates with and predicts CXCR4 co-receptor tropism switch in HIV-1 infection.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Viral Tropism*; HIV Infections/*immunology ; HIV Infections/*metabolism ; HIV-1/*physiology ; Receptors, CCR5/*metabolism ; Receptors, CXCR4/*metabolism; Adult ; Cross-Sectional Studies ; Female ; Humans ; Male

HIV-1 cell entry is mediated by binding to the CD4-receptor and chemokine co-receptors CCR5 (R5) or CXCR4 (X4). R5-tropic viruses are predominantly detected during early infection. A switch to X4-tropism often occurs during the course of infection. X4-tropism switching is strongly associated with accelerated disease progression and jeopardizes CCR5-based HIV-1 cure strategies. It is unclear whether host immunological factors play a causative role in tropism switching. We investigated the relationship between immunological factors and X4-tropism in a cross-sectional study in HIV-1 subtype C (HIV-1C)-infected patients and in a longitudinal HIV-1 subtype B (HIV-1B) seroconverter cohort. Principal component analysis identified a cluster of immunological markers (%HLA-DR ⁺ CD4 ⁺ T-cells, %CD38 ⁺ HLA-DR ⁺ CD4 ⁺ T-cells, %CD38 ⁺ HLA-DR ⁺ CD8 ⁺ T-cells, %CD70 ⁺ CD4 ⁺ T-cells, %CD169 ⁺ monocytes, and absolute CD4 ⁺ T-cell count) in HIV-1C patients that was independently associated with X4-tropism (aOR 1.044, 95% CI 1.003-1.087, p = 0.0392). Analysis of individual cluster contributors revealed strong correlations of two markers of T-cell activation (%HLA-DR ⁺ CD4 ⁺ T-cells, %HLA-DR ⁺ CD38 ⁺ CD4 ⁺ T-cells) with X4-tropism, both in HIV-1C patients (p = 0.01;p = 0.03) and HIV-1B patients (p = 0.0003;p = 0.0001). Follow-up data from HIV-1B patients subsequently revealed that T-cell activation precedes and independently predicts X4-tropism switching (aHR 1.186, 95% CI 1.065-1.321, p = 0.002), providing novel insights into HIV-1 pathogenesis and CCR5-based curative strategies.

Fauci, A. S. Host factors and the pathogenesis of HIV-induced disease. Nature 384, 529–534. https://doi.org/10.1038/384529a0 (1996). (PMID: 10.1038/384529a08955267)
Gupta, R. K. et al. HIV-1 remission following CCR5Delta32/Delta32 haematopoietic stem-cell transplantation. Nature 568, 244–248. https://doi.org/10.1038/s41586-019-1027-4 (2019). (PMID: 10.1038/s41586-019-1027-4308363797275870)
Liu, Z. et al. Genome editing of the HIV co-receptors CCR5 and CXCR4 by CRISPR-Cas9 protects CD4(+) T cells from HIV-1 infection. Cell. Biosci. 7, 47. https://doi.org/10.1186/s13578-017-0174-2 (2017). (PMID: 10.1186/s13578-017-0174-2289047455591563)
Koot, M. et al. Prognostic value of HIV-1 syncytium-inducing phenotype for rate of CD4+ cell depletion and progression to AIDS. Ann. Intern. Med. 118, 681–688 (1993). (PMID: 10.7326/0003-4819-118-9-199305010-00004)
Richman, D. D. & Bozzette, S. A. The impact of the syncytium-inducing phenotype of human immunodeficiency virus on disease progression. J. Infect. Dis 169, 968–974 (1994). (PMID: 10.1093/infdis/169.5.968)
Verhofstede, C., Nijhuis, M. & Vandekerckhove, L. Correlation of coreceptor usage and disease progression. Curr. Opin. HIV AIDS 7, 432–439. https://doi.org/10.1097/COH.0b013e328356f6f2 (2012). (PMID: 10.1097/COH.0b013e328356f6f222871636)
Zhu, T. et al. Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science 261, 1179–1181 (1993). (PMID: 10.1126/science.8356453)
Connor, R. I., Sheridan, K. E., Ceradini, D., Choe, S. & Landau, N. R. Change in coreceptor use correlates with disease progression in HIV-1–infected individuals. J. Exp. Med. 185, 621–628 (1997). (PMID: 10.1084/jem.185.4.621)
Schuitemaker, H. et al. Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. J. Virol 66, 1354–1360 (1992). (PMID: 10.1128/JVI.66.3.1354-1360.1992)
Connell, B. J. et al. Emergence of X4 usage among HIV-1 subtype C: evidence for an evolving epidemic in South Africa. AIDS 22, 896–899. https://doi.org/10.1097/QAD.0b013e3282f57f7a (2008). (PMID: 10.1097/QAD.0b013e3282f57f7a18427209)
Siddik, A. B. et al. Phenotypic co-receptor tropism and Maraviroc sensitivity in HIV-1 subtype C from East Africa. Sci. Rep. 8, 2363. https://doi.org/10.1038/s41598-018-20814-2 (2018). (PMID: 10.1038/s41598-018-20814-2294030645799384)
Singh, A. et al. Drug resistance and viral tropism in HIV-1 subtype C-infected patients in KwaZulu-Natal, South Africa: implications for future treatment options. J. Acquir. Immune Defic. Syndr. 58, 233–240. https://doi.org/10.1097/QAI.0b013e318228667f (2011). (PMID: 10.1097/QAI.0b013e318228667f217095693196677)
Moore, J. P., Kitchen, S. G., Pugach, P. & Zack, J. A. The CCR5 and CXCR4 coreceptors: central to understanding the transmission and pathogenesis of human immunodeficiency virus type 1 infection. AIDS Res. Hum. Retroviruses 20, 111–126. https://doi.org/10.1089/088922204322749567 (2004). (PMID: 10.1089/08892220432274956715000703)
Symons, J. et al. Maraviroc is able to inhibit dual-R5 viruses in a dual/mixed HIV-1-infected patient. J. Antimicrob. Chemother. 66, 890–895. https://doi.org/10.1093/jac/dkq535 (2011). (PMID: 10.1093/jac/dkq53521393136)
Thielen, A. et al. Mutations in gp41 are correlated with coreceptor tropism but do not improve prediction methods substantially. Antivir. Ther. 16, 319–328. https://doi.org/10.3851/IMP1769 (2011). (PMID: 10.3851/IMP176921555814)
Tsibris, A. M. et al. Quantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo. PLoS ONE 4, e5683. https://doi.org/10.1371/journal.pone.0005683 (2009). (PMID: 10.1371/journal.pone.0005683194790852682648)
Deeks, S. G. et al. International AIDS Society global scientific strategy: towards an HIV cure 2016. Nat. Med. 22, 839–850. https://doi.org/10.1038/nm.4108 (2016). (PMID: 10.1038/nm.4108274002645322797)
Kimata, J. T., Rice, A. P. & Wang, J. Challenges and strategies for the eradication of the HIV reservoir. Curr. Opin. Immunol. 42, 65–70. https://doi.org/10.1016/j.coi.2016.05.015 (2016). (PMID: 10.1016/j.coi.2016.05.015272886515086301)
Margolis, D. M., Garcia, J. V., Hazuda, D. J. & Haynes, B. F. Latency reversal and viral clearance to cure HIV-1. Science 353, 6517. https://doi.org/10.1126/science.aaf6517 (2016). (PMID: 10.1126/science.aaf6517)
Siliciano, J. D. & Siliciano, R. F. Recent developments in the effort to cure HIV infection: going beyond N = 1. J. Clin. Invest. 126, 409–414. https://doi.org/10.1172/JCI86047 (2016). (PMID: 10.1172/JCI86047268296224731192)
Kwong, P. D. et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393, 648–659. https://doi.org/10.1038/31405 (1998). (PMID: 10.1038/3140596416775629912)
Jensen, M. A., Coetzer, M. & van ’t Wout, A. B., Morris, L. & Mullins, J. I. ,. A reliable phenotype predictor for human immunodeficiency virus type 1 subtype C based on envelope V3 sequences. J. Virol 80, 4698–4704. https://doi.org/10.1128/JVI.80.10.4698-4704.2006 (2006). (PMID: 10.1128/JVI.80.10.4698-4704.2006166412631472078)
Lengauer, T., Sander, O., Sierra, S., Thielen, A. & Kaiser, R. Bioinformatics prediction of HIV coreceptor usage. Nat. Biotechnol. 25, 1407–1410. https://doi.org/10.1038/nbt1371 (2007). (PMID: 10.1038/nbt137118066037)
Mosier, D. E. How HIV changes its tropism: evolution and adaptation?. Curr. Opin. HIV AIDS 4, 125–130. https://doi.org/10.1097/COH.0b013e3283223d61 (2009). (PMID: 10.1097/COH.0b013e3283223d61193399512697388)
Deeks, S. G. et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 104, 942–947. https://doi.org/10.1182/blood-2003-09-3333 (2004). (PMID: 10.1182/blood-2003-09-333315117761)
Giorgi, J. V. et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J. Infect. Dis 179, 859–870. https://doi.org/10.1086/314660 (1999). (PMID: 10.1086/31466010068581)
Giorgi, J. V. et al. Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study. J. Acquir. Immune Defic. Syndr 6, 904–912 (1993).
Utay, N. S. & Hunt, P. W. Role of immune activation in progression to AIDS. Curr. Opin. HIV AIDS 11, 131–137. https://doi.org/10.1097/COH.0000000000000242 (2016). (PMID: 10.1097/COH.0000000000000242267314304750472)
Joseph, S. B. & Swanstrom, R. The evolution of HIV-1 entry phenotypes as a guide to changing target cells. J. Leukoc. Biol. 103, 421–431. https://doi.org/10.1002/JLB.2RI0517-200R (2018). (PMID: 10.1002/JLB.2RI0517-200R29389021)
Lee, B., Sharron, M., Montaner, L. J., Weissman, D. & Doms, R. W. Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc. Natl. Acad. Sci. U S A 96, 5215–5220 (1999). (PMID: 10.1073/pnas.96.9.5215)
Bader, J. et al. Correlating HIV tropism with immunological response under combination antiretroviral therapy. HIV Med. 17, 615–622. https://doi.org/10.1111/hiv.12365 (2016). (PMID: 10.1111/hiv.1236526991140)
Brieu, N., Portales, P., Carles, M. J. & Corbeau, P. Interleukin-7 induces HIV type 1 R5-to-X4 switch. Blood 117, 2073–2074. https://doi.org/10.1182/blood-2010-10-311860 (2011). (PMID: 10.1182/blood-2010-10-31186021310936)
Fiser, A. L. et al. Pairwise comparison of isogenic HIV-1 viruses: R5 phenotype replicates more efficiently than X4 phenotype in primary CD4+ T cells expressing physiological levels of CXCR4. J. Acquir. Immune. Defic. Syndr. 53, 162–166. https://doi.org/10.1097/QAI.0b013e3181c72033 (2010). (PMID: 10.1097/QAI.0b013e3181c7203320051874)
Fiser, A. L. et al. High CD4(+) T-cell surface CXCR4 density as a risk factor for R5 to X4 switch in the course of HIV-1 infection. J. Acquir. Immune. Defic. Syndr. 55, 529–535. https://doi.org/10.1097/QAI.0b013e3181f25bab (2010). (PMID: 10.1097/QAI.0b013e3181f25bab20861743)
van Rij, R. P. et al. Differential coreceptor expression allows for independent evolution of non-syncytium-inducing and syncytium-inducing HIV-1. J. Clin. Invest. 106, 1569 (2000). (PMID: 10.1172/JCI7953C1)
Gonzalez, N. et al. SDF-1/CXCL12 production by mature dendritic cells inhibits the propagation of X4-tropic HIV-1 isolates at the dendritic cell-T-cell infectious synapse. J. Virol 84, 4341–4351. https://doi.org/10.1128/JVI.02449-09 (2010). (PMID: 10.1128/JVI.02449-09201816952863755)
Sarrami-Forooshani, R. et al. Human immature Langerhans cells restrict CXCR4-using HIV-1 transmission. Retrovirology 11, 52. https://doi.org/10.1186/1742-4690-11-52 (2014). (PMID: 10.1186/1742-4690-11-52249901634227116)
Bunnik, E. M., Quakkelaar, E. D., van Nuenen, A. C., Boeser-Nunnink, B. & Schuitemaker, H. Increased neutralization sensitivity of recently emerged CXCR4-using human immunodeficiency virus type 1 strains compared to coexisting CCR5-using variants from the same patient. J. Virol. 81, 525–531. https://doi.org/10.1128/JVI.01983-06 (2007). (PMID: 10.1128/JVI.01983-0617079299)
Bader, J. et al. Therapeutic immune recovery and reduction of CXCR4-tropic HIV-1. Clin. Infect. Dis. 64, 295–300. https://doi.org/10.1093/cid/ciw737 (2017). (PMID: 10.1093/cid/ciw73727838645)
Hemelaar, J. et al. Global trends in molecular epidemiology of HIV-1 during 2000–2007. AIDS 25, 679–689. https://doi.org/10.1097/QAD.0b013e328342ff93 (2011). (PMID: 10.1097/QAD.0b013e328342ff93212974243755761)
Abebe, A. et al. HIV-1 subtype C syncytium- and non-syncytium-inducing phenotypes and coreceptor usage among Ethiopian patients with AIDS. AIDS 13, 1305–1311 (1999). (PMID: 10.1097/00002030-199907300-00006)
Ataher, Q. et al. The epidemiology and clinical correlates of HIV-1 co-receptor tropism in non-subtype B infections from India, Uganda and South Africa. J. Int. AIDS Soc. 15, 2. https://doi.org/10.1186/1758-2652-15-2 (2012). (PMID: 10.1186/1758-2652-15-2222810973298508)
Bjorndal, A., Sonnerborg, A., Tscherning, C., Albert, J. & Fenyo, E. M. Phenotypic characteristics of human immunodeficiency virus type 1 subtype C isolates of Ethiopian AIDS patients. AIDS Res. Hum. Retroviruses 15, 647–653. https://doi.org/10.1089/088922299310944 (1999). (PMID: 10.1089/08892229931094410331443)
Cecilia, D. et al. Absence of coreceptor switch with disease progression in human immunodeficiency virus infections in India. Virology 271, 253–258. https://doi.org/10.1006/viro.2000.0297 (2000). (PMID: 10.1006/viro.2000.029710860879)
Jakobsen, M. R. et al. Longitudinal analysis of CCR5 and CXCR4 usage in a cohort of antiretroviral therapy-naive subjects with progressive HIV-1 subtype C infection. PLoS ONE 8, e65950. https://doi.org/10.1371/journal.pone.0065950 (2013). (PMID: 10.1371/journal.pone.0065950238240433688867)
Johnston, E. R. et al. High frequency of syncytium-inducing and CXCR4-tropic viruses among human immunodeficiency virus type 1 subtype C-infected patients receiving antiretroviral treatment. J. Virol 77, 7682–7688 (2003). (PMID: 10.1128/JVI.77.13.7682-7688.2003)
Lin, N. H. et al. Prevalence and clinical associations of CXCR4-using HIV-1 among treatment-naive subtype C-infected women in Botswana. J. Acquir. Immune Defic. Syndr. 57, 46–50. https://doi.org/10.1097/QAI.0b013e318214fe27 (2011). (PMID: 10.1097/QAI.0b013e318214fe27213465883353541)
Ndung’u, T. et al. HIV-1 subtype C in vitro growth and coreceptor utilization. Virology 347, 247–260. https://doi.org/10.1016/j.virol.2005.11.047 (2006). (PMID: 10.1016/j.virol.2005.11.04716406460)
Ping, L. H. et al. Characterization of V3 sequence heterogeneity in subtype C human immunodeficiency virus type 1 isolates from Malawi: underrepresentation of X4 variants. J. Virol 73, 6271–6281 (1999). (PMID: 10.1128/JVI.73.8.6271-6281.1999)
McGovern, R. A. et al. Maraviroc treatment in non-R5-HIV-1-infected patients results in the selection of extreme CXCR4-using variants with limited effect on the total viral setpoint. J. Antimicrob. Chemother 68, 2007–2014. https://doi.org/10.1093/jac/dkt153 (2013). (PMID: 10.1093/jac/dkt15323677920)
Westby, M. et al. Emergence of CXCR4-using human immunodeficiency virus type 1 (HIV-1) variants in a minority of HIV-1-infected patients following treatment with the CCR5 antagonist maraviroc is from a pretreatment CXCR4-using virus reservoir. J. Virol 80, 4909–4920. https://doi.org/10.1128/JVI.80.10.4909-4920.2006 (2006). (PMID: 10.1128/JVI.80.10.4909-4920.2006166412821472081)
Verheyen, J. et al. Rapid rebound of a preexisting CXCR4-tropic human immunodeficiency virus variant after allogeneic transplantation with CCR5 Delta32 homozygous stem cells. Clin. Infect. Dis. 68, 684–687. https://doi.org/10.1093/cid/ciy565 (2019). (PMID: 10.1093/cid/ciy56530020413)
Hazenberg, M. D. et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS 17, 1881–1888. https://doi.org/10.1097/01.aids.0000076311.76477.6e (2003). (PMID: 10.1097/01.aids.0000076311.76477.6e12960820)
Symons, J. et al. Impact of triplicate testing on HIV genotypic tropism prediction in routine clinical practice. Clin. Microbiol. Infect. 18, 606–612. https://doi.org/10.1111/j.1469-0691.2011.03631.x (2012). (PMID: 10.1111/j.1469-0691.2011.03631.x21906210)
Vandekerckhove, L. P. et al. European guidelines on the clinical management of HIV-1 tropism testing. Lancet Infect. Dis. 11, 394–407. https://doi.org/10.1016/S1473-3099(10)70319-4 (2011). (PMID: 10.1016/S1473-3099(10)70319-421429803)
Swenson, L. C. et al. Genotypic analysis of the V3 region of HIV from virologic nonresponders to maraviroc-containing regimens reveals distinct patterns of failure. Antimicrob. Agents Chemother. 57, 6122–6130. https://doi.org/10.1128/AAC.01534-13 (2013). (PMID: 10.1128/AAC.01534-13240806553837924)
Swenson, L. C. et al. Deep sequencing to infer HIV-1 co-receptor usage: application to three clinical trials of maraviroc in treatment-experienced patients. J. Infect. Dis. 203, 237–245. https://doi.org/10.1093/infdis/jiq030 (2011). (PMID: 10.1093/infdis/jiq030212888243071057)
Swenson, L. C. et al. Deep V3 sequencing for HIV type 1 tropism in treatment-naive patients: a reanalysis of the MERIT trial of maraviroc. Clin. Infect. Dis. 53, 732–742. https://doi.org/10.1093/cid/cir493 (2011). (PMID: 10.1093/cid/cir49321890778)
Spijkerman, I., de Wolf, F., Langendam, M., Schuitemaker, H. & Coutinho, R. Emergence of syncytium-inducing human immunodeficiency virus type 1 variants coincides with a transient increase in viral RNA level and is an independent predictor for progression to AIDS. J. Infect. Dis. 178, 397–403 (1998). (PMID: 10.1086/515627)
de Jager, W. et al. Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study. Ann. Rheum. Dis. 66, 589–598. https://doi.org/10.1136/ard.2006.061853 (2007). (PMID: 10.1136/ard.2006.06185317170049)
de Jager, W., Prakken, B. J., Bijlsma, J. W., Kuis, W. & Rijkers, G. T. Improved multiplex immunoassay performance in human plasma and synovial fluid following removal of interfering heterophilic antibodies. J. Immunol. Methods 300, 124–135. https://doi.org/10.1016/j.jim.2005.03.009 (2005). (PMID: 10.1016/j.jim.2005.03.00915896801)
Hydes, T. J. et al. The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways. Tissue Antigens 86, 267–275. https://doi.org/10.1111/tan.12650 (2015). (PMID: 10.1111/tan.12650263810474858811)

No. 331131 United Kingdom MCCC_ Marie Curie

0 (CXCR4 protein, human)
0 (Receptors, CCR5)
0 (Receptors, CXCR4)

Date Created: 20200928 Date Completed: 20201228 Latest Revision: 20210928

20231215

PMC7522993

10.1038/s41598-020-71699-z

32985522