HIV-1 Evades Virus-specific IgG2 and IgA Responses by Targeting Systemic and Intestinal B Cells Via Long-range Intercellular Conduits

Overview

Journal Nat Immunol

Date 2009 Aug 4

PMID 19648924

Citations 179

Authors

Weifeng Xu

Paul A Santini

John S Sullivan

Bing He

Meimei Shan

Susan C Ball

Wayne B Dyer

Thomas J Ketas

Amy Chadburn

Leona Cohen-Gould

Daniel M Knowles

April Chiu

Rogier W Sanders

Kang Chen

Andrea Cerutti

Affiliations

Soon will be listed here.

Abstract

Contact-dependent communication between immune cells generates protection but also facilitates viral spread. Here we found that macrophages formed long-range actin-propelled conduits in response to negative factor (Nef), a human immunodeficiency virus type 1 (HIV-1) protein with immunosuppressive functions. Conduits attenuated immunoglobulin G2 (IgG2) and IgA class switching in systemic and intestinal lymphoid follicles by shuttling Nef from infected macrophages to B cells through a guanine-exchange factor-dependent pathway involving the amino-terminal anchor, central core and carboxy-terminal flexible loop of Nef. By showing stronger virus-specific IgG2 and IgA responses in patients with Nef-deficient virions, our data suggest that HIV-1 exploits intercellular 'highways' as a 'Trojan horse' to deliver Nef to B cells and evade humoral immunity systemically and at mucosal sites of entry.

Citing Articles

SIV-specific neutralizing antibody induction following selection of a PI3K drive-attenuated variant.

Yamamoto H, Matano T Elife. 2025; 12.

PMID: 40029304 PMC: 11875539. DOI: 10.7554/eLife.88849.

The Impact of HIV on B Cell Compartment and Its Implications for COVID-19 Vaccinations in People with HIV.

Wang L, Vulesevic B, Vigano M, Assadiq A, Kang K, Fernandez C Vaccines (Basel). 2025; 12(12.

PMID: 39772034 PMC: 11679862. DOI: 10.3390/vaccines12121372.

Gastrointestinal germinal center B cell depletion and reduction in IgA plasma cells in HIV-1 infection.

Cossarini F, Shang J, Krek A, Al-Taie Z, Hou R, Canales-Herrerias P Sci Immunol. 2024; 9(100):eado0090.

PMID: 39454027 PMC: 11557871. DOI: 10.1126/sciimmunol.ado0090.

Sustained Long-Term Decline in Anti-HCV Neutralizing Antibodies in HIV/HCV-Coinfected Patients Five Years after HCV Therapy: A Retrospective Study.

Sepulveda-Crespo D, Volpi C, Amigot-Sanchez R, Yelamos M, Diez C, Gomez J Pharmaceuticals (Basel). 2024; 17(9).

PMID: 39338314 PMC: 11434851. DOI: 10.3390/ph17091152.

Role of cellular effectors in the induction and maintenance of IgA responses leading to protective immunity against enteric bacterial pathogens.

Carreto-Binaghi L, Sztein M, Booth J Front Immunol. 2024; 15:1446072.

PMID: 39324143 PMC: 11422102. DOI: 10.3389/fimmu.2024.1446072.

References

Costa L, Chen N, Lopes A, Aguiar R, Tanuri A, Plemenitas A . Interactions between Nef and AIP1 proliferate multivesicular bodies and facilitate egress of HIV-1. Retrovirology. 2006; 3:33. PMC: 1526754. DOI: 10.1186/1742-4690-3-33. View

Davis D . Intercellular transfer of cell-surface proteins is common and can affect many stages of an immune response. Nat Rev Immunol. 2007; 7(3):238-43. DOI: 10.1038/nri2020. View

Sherer N, Mothes W . Cytonemes and tunneling nanotubules in cell-cell communication and viral pathogenesis. Trends Cell Biol. 2008; 18(9):414-20. PMC: 2628975. DOI: 10.1016/j.tcb.2008.07.003. View

Blagoveshchenskaya A, Thomas L, Feliciangeli S, Hung C, Thomas G . HIV-1 Nef downregulates MHC-I by a PACS-1- and PI3K-regulated ARF6 endocytic pathway. Cell. 2003; 111(6):853-66. DOI: 10.1016/s0092-8674(02)01162-5. View

Qiao X, He B, Chiu A, Knowles D, Chadburn A, Cerutti A . Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells. Nat Immunol. 2006; 7(3):302-10. DOI: 10.1038/ni1302. View

Santa-Marta M, Aires da Silva F, Fonseca A, Rato S, Goncalves J . HIV-1 Vif protein blocks the cytidine deaminase activity of B-cell specific AID in E. coli by a similar mechanism of action. Mol Immunol. 2006; 44(4):583-90. DOI: 10.1016/j.molimm.2006.02.005. View

Klein U, Casola S, Cattoretti G, Shen Q, Lia M, Mo T . Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nat Immunol. 2006; 7(7):773-82. DOI: 10.1038/ni1357. View

Mestecky J, Jackson S, Moldoveanu Z, Nesbit L, Kulhavy R, Prince S . Paucity of antigen-specific IgA responses in sera and external secretions of HIV-type 1-infected individuals. AIDS Res Hum Retroviruses. 2004; 20(9):972-88. DOI: 10.1089/aid.2004.20.972. View

Thoulouze M, Sol-Foulon N, Blanchet F, Dautry-Varsat A, Schwartz O, Alcover A . Human immunodeficiency virus type-1 infection impairs the formation of the immunological synapse. Immunity. 2006; 24(5):547-61. DOI: 10.1016/j.immuni.2006.02.016. View

10.

Burton D, Desrosiers R, Doms R, Koff W, Kwong P, Moore J . HIV vaccine design and the neutralizing antibody problem. Nat Immunol. 2004; 5(3):233-6. DOI: 10.1038/ni0304-233. View

11.

Conboy I, Manoli D, Mhaiskar V, Jones P . Calcineurin and vacuolar-type H+-ATPase modulate macrophage effector functions. Proc Natl Acad Sci U S A. 1999; 96(11):6324-9. PMC: 26880. DOI: 10.1073/pnas.96.11.6324. View

12.

Litinskiy M, Nardelli B, Hilbert D, He B, Schaffer A, Casali P . DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol. 2002; 3(9):822-9. PMC: 4621779. DOI: 10.1038/ni829. View

13.

Junt T, Moseman E, Iannacone M, Massberg S, Lang P, Boes M . Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature. 2007; 450(7166):110-4. DOI: 10.1038/nature06287. View

14.

Poudrier J, Weng X, Kay D, Pare G, Calvo E, Hanna Z . The AIDS disease of CD4C/HIV transgenic mice shows impaired germinal centers and autoantibodies and develops in the absence of IFN-gamma and IL-6. Immunity. 2001; 15(2):173-85. DOI: 10.1016/s1074-7613(01)00177-7. View

15.

Schafer F, Kewenig S, Stolte N, Stahl-Hennig C, Stallmach A, Kaup F . Lack of simian immunodeficiency virus (SIV) specific IgA response in the intestine of SIV infected rhesus macaques. Gut. 2002; 50(5):608-14. PMC: 1773198. DOI: 10.1136/gut.50.5.608. View

16.

Begum N, Izumi N, Nishikori M, Nagaoka H, Shinkura R, Honjo T . Requirement of non-canonical activity of uracil DNA glycosylase for class switch recombination. J Biol Chem. 2006; 282(1):731-42. DOI: 10.1074/jbc.M607439200. View

17.

Muratori C, Sistigu A, Ruggiero E, Falchi M, Bacigalupo I, Palladino C . Macrophages transmit human immunodeficiency virus type 1 products to CD4-negative cells: involvement of matrix metalloproteinase 9. J Virol. 2007; 81(17):9078-87. PMC: 1951421. DOI: 10.1128/JVI.00675-07. View

18.

Binley J, Klasse P, Cao Y, Jones I, Markowitz M, Ho D . Differential regulation of the antibody responses to Gag and Env proteins of human immunodeficiency virus type 1. J Virol. 1997; 71(4):2799-809. PMC: 191404. DOI: 10.1128/JVI.71.4.2799-2809.1997. View

19.

He B, Qiao X, Klasse P, Chiu A, Chadburn A, Knowles D . HIV-1 envelope triggers polyclonal Ig class switch recombination through a CD40-independent mechanism involving BAFF and C-type lectin receptors. J Immunol. 2006; 176(7):3931-41. DOI: 10.4049/jimmunol.176.7.3931. View

20.

Popovic M, Tenner-Racz K, Pelser C, Stellbrink H, van Lunzen J, Lewis G . Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 2005; 102(41):14807-12. PMC: 1253583. DOI: 10.1073/pnas.0506857102. View