HIV Infection of Macrophages: Implications for Pathogenesis and Cure

Main Article Content

Kiera Leigh Clayton
Victor Garcia
Janice E. Clements
Bruce D. Walker


Although CD4+ T cells represent the major reservoir of persistent HIV and SIV infection, accumulating evidence suggests that macrophages also contribute. However, investigations of the role of macrophages are often underrepresented at HIV pathogenesis and cure meetings. This was the impetus for a scientific workshop dedicated to this area of study, held in Cambridge, MA in January 2017. The workshop brought together experts in the fields of HIV/SIV immunology/virology, macrophage biology and immunology, and animal models of HIV/SIV infection to facilitate discussions regarding the role of macrophages as a physiologically relevant viral reservoir, and the implications of macrophage infection for HIV pathogenesis and cure strategies. An emerging consensus that infected macrophages likely persist in the setting of combination antiretroviral therapy, driving persistent inflammation and contributing to the viral reservoir, indicate the importance of addressing macrophages as well as CD4+ T cells with future therapeutic strategies.


Download data is not yet available.

Article Details



1. Swirski FK, Robbins CS, Nahrendorf M. Development and Function of Arterial and Cardiac Macrophages. Trends Immunol. 2016;37(1):32-40. PubMed PMID: 26748179. Pubmed Central PMCID: PMC4706986. 10.1016/

2. Ensan S, Li A, Besla R, Degousee N, Cosme J, Roufaiel M, Shikatani EA, El-Maklizi M, Williams JW, Robins L, Li C, Lewis B, Yun TJ, Lee JS, Wieghofer P, Khattar R, Farrokhi K, Byrne J, Ouzounian M, Zavitz CC, Levy GA, Bauer CM, Libby P, Husain M, Swirski FK, Cheong C, Prinz M, Hilgendorf I, Randolph GJ, Epelman S, Gramolini AO, Cybulsky MI, Rubin BB, Robbins CS. Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth. Nat Immunol. 2016;17(2):159-68. PubMed PMID: 26642357. 10.1038/ni.3343

3. Kuritzkes DR. Why cure, why now? J Med Ethics. 2017;43(2):67-70. PubMed PMID: 27273887. Pubmed Central PMCID: PMC5293855. 10.1136/medethics-2015-103113

4. Delagreverie HM, Delaugerre C, Lewin SR, Deeks SG, Li JZ. Ongoing Clinical Trials of Human Immunodeficiency Virus Latency-Reversing and Immunomodulatory Agents. Open Forum Infect Dis. 2016;3(4):ofw189. PubMed PMID: 27757411. Pubmed Central PMCID: PMC5066458. 10.1093/ofid/ofw189

5. Bar KJ, Sneller MC, Harrison LJ, Justement JS, Overton ET, Petrone ME, Salantes DB, Seamon CA, Scheinfeld B, Kwan RW, Learn GH, Proschan MA, Kreider EF, Blazkova J, Bardsley M, Refsland EW, Messer M, Clarridge KE, Tustin NB, Madden PJ, Oden K, O'Dell SJ, Jarocki B, Shiakolas AR, Tressler RL, Doria-Rose NA, Bailer RT, Ledgerwood JE, Capparelli EV, Lynch RM, Graham BS, Moir S, Koup RA, Mascola JR, Hoxie JA, Fauci AS, Tebas P, Chun TW. Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption. N Engl J Med. 2016;375(21):2037-50. PubMed PMID: 27959728. 10.1056/NEJMoa1608243

6. Churchill MJ, Deeks SG, Margolis DM, Siliciano RF, Swanstrom R. HIV reservoirs: what, where and how to target them. Nat Rev Microbiol. 2016;14(1):55-60. PubMed PMID: 26616417. 10.1038/nrmicro.2015.5

7. Ananworanich J, Chomont N, Eller LA, Kroon E, Tovanabutra S, Bose M, Nau M, Fletcher JL, Tipsuk S, Vandergeeten C, O'Connell RJ, Pinyakorn S, Michael N, Phanuphak N, Robb ML, Rv, groups RSs. HIV DNA Set Point is Rapidly Established in Acute HIV Infection and Dramatically Reduced by Early ART. EBioMedicine. 2016;11:68-72. PubMed PMID: 27460436. Pubmed Central PMCID: PMC5049918. 10.1016/j.ebiom.2016.07.024

8. Deeks SG, Lewin SR, Ross AL, Ananworanich J, Benkirane M, Cannon P, Chomont N, Douek D, Lifson JD, Lo YR, Kuritzkes D, Margolis D, Mellors J, Persaud D, Tucker JD, Barre-Sinoussi F, International ASTaCWG, Alter G, Auerbach J, Autran B, Barouch DH, Behrens G, Cavazzana M, Chen Z, Cohen EA, Corbelli GM, Eholie S, Eyal N, Fidler S, Garcia L, Grossman C, Henderson G, Henrich TJ, Jefferys R, Kiem HP, McCune J, Moodley K, Newman PA, Nijhuis M, Nsubuga MS, Ott M, Palmer S, Richman D, Saez-Cirion A, Sharp M, Siliciano J, Silvestri G, Singh J, Spire B, Taylor J, Tolstrup M, Valente S, van Lunzen J, Walensky R, Wilson I, Zack J. International AIDS Society global scientific strategy: towards an HIV cure 2016. Nat Med. 2016;22(8):839-50. PubMed PMID: 27400264. Pubmed Central PMCID: PMC5322797. 10.1038/nm.4108

9. Lederman MM, Cannon PM, Currier JS, June CH, Kiem HP, Kuritzkes DR, Lewin SR, Margolis DM, McCune JM, Mellors JW, Schacker TW, Sekaly RP, Tebas P, Walker BD, Douek DC. A Cure for HIV Infection: "Not in My Lifetime" or "Just Around the Corner"? Pathog Immun. 2016;1(1):154-64. PubMed PMID: 27668293. Pubmed Central PMCID: PMC5033048. 10.20411/pai.v1i1.133

10. Lee SA, Deeks SG. The Benefits of Early Antiretroviral Therapy for HIV Infection: How Early is Early Enough? EBioMedicine. 2016;11:7-8. PubMed PMID: 27515690. Pubmed Central PMCID: PMC5049928. 10.1016/j.ebiom.2016.08.009

11. Baxter AE, Russell RA, Duncan CJ, Moore MD, Willberg CB, Pablos JL, Finzi A, Kaufmann DE, Ochsenbauer C, Kappes JC, Groot F, Sattentau QJ. Macrophage infection via selective capture of HIV-1-infected CD4+ T cells. Cell Host Microbe. 2014;16(6):711-21. PubMed PMID: 25467409. Pubmed Central PMCID: PMC4271767. 10.1016/j.chom.2014.10.010

12. Sattentau QJ, Stevenson M. Macrophages and HIV-1: An Unhealthy Constellation. Cell Host Microbe. 2016;19(3):304-10. PubMed PMID: 26962941. 10.1016/j.chom.2016.02.013

13. Micci L, Alvarez X, Iriele RI, Ortiz AM, Ryan ES, McGary CS, Deleage C, McAtee BB, He T, Apetrei C, Easley K, Pahwa S, Collman RG, Derdeyn CA, Davenport MP, Estes JD, Silvestri G, Lackner AA, Paiardini M. CD4 depletion in SIV-infected macaques results in macrophage and microglia infection with rapid turnover of infected cells. PLoS Pathog. 2014;10(10):e1004467. PubMed PMID: 25356757. Pubmed Central PMCID: PMC4214815. 10.1371/journal.ppat.1004467

14. Cai Y, Sugimoto C, Liu DX, Midkiff CC, Alvarez X, Lackner AA, Kim WK, Didier ES, Kuroda MJ. Increased monocyte turnover is associated with interstitial macrophage accumulation and pulmonary tissue damage in SIV-infected rhesus macaques. J Leukoc Biol. 2015;97(6):1147-53. PubMed PMID: 25780057. Pubmed Central PMCID: PMC4763878. 10.1189/jlb.4A0914-441R

15. DiNapoli SR, Ortiz AM, Wu F, Matsuda K, Twigg HL, 3rd, Hirsch VM, Knox K, Brenchley JM. Tissue-resident macrophages can contain replication-competent virus in antiretroviral-naive, SIV-infected Asian macaques. JCI Insight. 2017;2(4):e91214. PubMed PMID: 28239657. Pubmed Central PMCID: PMC5313072 exists. 10.1172/jci.insight.91214

16. Graziano F, Vicenzi E, Poli G. Plastic restriction of HIV-1 replication in human macrophages derived from M1/M2 polarized monocytes. J Leukoc Biol. 2016;100(5):1147-53. PubMed PMID: 27365533. 10.1189/jlb.4AB0316-158R

17. Zaritsky LA, Gama L, Clements JE. Canonical type I IFN signaling in simian immunodeficiency virus-infected macrophages is disrupted by astrocyte-secreted CCL2. J Immunol. 2012;188(8):3876-85. PubMed PMID: 22407919. Pubmed Central PMCID: PMC3343693. 10.4049/jimmunol.1103024

18. Alammar L, Gama L, Clements JE. Simian immunodeficiency virus infection in the brain and lung leads to differential type I IFN signaling during acute infection. J Immunol. 2011;186(7):4008-18. PubMed PMID: 21368232. Pubmed Central PMCID: PMC3076806. 10.4049/jimmunol.1003757

19. Corley MJ, Dye C, D'Antoni ML, Byron MM, Yo KL, Lum-Jones A, Nakamoto B, Valcour V, SahBandar I, Shikuma CM, Ndhlovu LC, Maunakea AK. Comparative DNA Methylation Profiling Reveals an Immunoepigenetic Signature of HIV-related Cognitive Impairment. Sci Rep. 2016;6:33310. PubMed PMID: 27629381. Pubmed Central PMCID: PMC5024304. 10.1038/srep33310

20. Vojnov L, Martins MA, Bean AT, Veloso de Santana MG, Sacha JB, Wilson NA, Bonaldo MC, Galler R, Stevenson M, Watkins DI. The majority of freshly sorted simian immunodeficiency virus (SIV)-specific CD8(+) T cells cannot suppress viral replication in SIV-infected macrophages. J Virol. 2012;86(8):4682-7. PubMed PMID: 22318140. Pubmed Central PMCID: 3318662. 10.1128/JVI.06324-11

21. Rainho JN, Martins MA, Cunyat F, Watkins IT, Watkins DI, Stevenson M. Nef Is Dispensable for Resistance of Simian Immunodeficiency Virus-Infected Macrophages to CD8+ T Cell Killing. J Virol. 2015;89(20):10625-36. PubMed PMID: 26269172. Pubmed Central PMCID: 4580207. 10.1128/JVI.01699-15

22. Honeycutt JB, Wahl A, Baker C, Spagnuolo RA, Foster J, Zakharova O, Wietgrefe S, Caro-Vegas C, Madden V, Sharpe G, Haase AT, Eron JJ, Garcia JV. Macrophages sustain HIV replication in vivo independently of T cells. J Clin Invest. 2016;126(4):1353-66. PubMed PMID: 26950420. Pubmed Central PMCID: PMC4811134. 10.1172/JCI84456

23. Avalos CR, Price SL, Forsyth ER, Pin JN, Shirk EN, Bullock BT, Queen SE, Li M, Gellerup D, O'Connor SL, Zink MC, Mankowski JL, Gama L, Clements JE. Quantitation of Productively Infected Monocytes and Macrophages of Simian Immunodeficiency Virus-Infected Macaques. J Virol. 2016;90(12):5643-56. PubMed PMID: 27030272. Pubmed Central PMCID: PMC4886778. 10.1128/JVI.00290-16

24. Dinoso JB, Rabi SA, Blankson JN, Gama L, Mankowski JL, Siliciano RF, Zink MC, Clements JE. A simian immunodeficiency virus-infected macaque model to study viral reservoirs that persist during highly active antiretroviral therapy. J Virol. 2009;83(18):9247-57. PubMed PMID: 19570871. Pubmed Central PMCID: PMC2738256. 10.1128/JVI.00840-09

Most read articles by the same author(s)