Front Immunol. 2013 Apr 24;4:95. doi: 10.3389/fimmu.2013.00095. eCollection 2013.
Innate and Adaptive Immunity in Long-Term Non-Progression in HIV Disease.
Frontiers in immunology
John Zaunders, David van Bockel
Affiliations
Affiliations
- Centre for Applied Medical Research, St Vincent's Hospital Darlinghurst, NSW, Australia.
PMID: 23630526
PMCID: PMC3633949 DOI: 10.3389/fimmu.2013.00095
Abstract
Long-term non-progressors (LTNP) were identified after 10-15 years of the epidemic, and have been the subject of intense investigation ever since. In a small minority of cases, infection with nef/3'LTR deleted attenuated viral strains allowed control over viral replication. A common feature of LTNP is the readily detected proliferation of CD4 T-cells in vitro, in response to p24. In some cases, the responding CD4 T-cells have cytotoxic effector function and may target conserved p24 epitopes, similar to the CD8 T-cells described below. LTNP may also carry much lower HIV DNA burden in key CD4 subsets, presumably resulting from lower viral replication during primary infection. Some studies, but not others, suggest that LTNP have CD4 T-cells that are relatively resistant to HIV infection in vitro. One possible mechanism may involve up-regulation of the cell cycle regulator p21/waf in CD4 T-cells from LTNP. Delayed progression in Caucasian LTNP is also partly associated with heterozygosity of the Δ32 CCR5 allele, probably through decreased expression of CCR5 co-receptor on CD4 T-cells. However, in approximately half of Caucasian LTNP, two host genotypes, namely HLA-B57 and HLA-B27, are associated with viral control. Immunodominant CD8 T-cells from these individuals target epitopes in p24 that are highly conserved, and escape mutations have significant fitness costs to the virus. Furthermore, recent studies have suggested that these CD8 T-cells from LTNP, but not from HLA-B27 or HLA-B57 progressors, can cross-react with intermediate escape mutations, preventing full escape via compensatory mutations. Humoral immunity appears to play little part in LTNP subjects, since broadly neutralizing antibodies are rare, even amongst slow progressors. Recent genome-wide comparisons between LTNP and progressors have confirmed the HLA-B57, HLA-B27, and delta32 CCR5 allelic associations, plus indicated a role for HLA-C/KIR interactions, but have not revealed any new genotypes so far. Nevertheless, it is hoped that studying the mechanisms of intracellular restriction factors, such as the recently identified SAMHD1, will lead to a better understanding of non-progression.
Keywords: HIV-1; cell-mediated immunity; cytotoxic T lymphocytes; elite controllers; long-term non-progressors
References
- Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8869-73 - PubMed
- Curr Opin HIV AIDS. 2011 May;6(3):151-6 - PubMed
- AIDS. 1991 Jan;5(1):1-14 - PubMed
- J Immunol. 2006 May 15;176(10):6130-46 - PubMed
- Blood. 2012 May 17;119(20):4645-55 - PubMed
- J Intern Med. 2009 Jan;265(1):29-42 - PubMed
- AIDS Res Hum Retroviruses. 1996 Dec 10;12(18):1691-8 - PubMed
- Nat Genet. 2002 Aug;31(4):429-34 - PubMed
- Curr Drug Targets. 2006 Dec;7(12):1571-82 - PubMed
- Sci Transl Med. 2012 Feb 29;4(123):123ra25 - PubMed
- Front Microbiol. 2012 Mar 15;3:97 - PubMed
- Nature. 2000 Sep 28;407(6803):523-6 - PubMed
- AIDS. 2005 Nov 18;19(17):2001-7 - PubMed
- J Virol. 2000 May;74(9):4361-76 - PubMed
- Nat Med. 2010 Apr;16(4):452-9 - PubMed
- Lancet. 1999 Nov 20;354(9192):1782-5 - PubMed
- Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):E689-98 - PubMed
- Retrovirology. 2012 Nov 06;9:91 - PubMed
- J Infect Dis. 2008 Jan 1;197(1):126-33 - PubMed
- Blood. 2004 Mar 15;103(6):2238-47 - PubMed
- Cell. 1990 Apr 20;61(2):213-22 - PubMed
- Curr Opin Immunol. 1996 Aug;8(4):472-7 - PubMed
- J Infect Dis. 1998 Dec;178(6):1812-5 - PubMed
- AIDS Res Hum Retroviruses. 1999 Nov 20;15(17):1519-27 - PubMed
- J Virol. 2010 Jun;84(11):5540-9 - PubMed
- J Virol. 2006 Oct;80(20):10151-61 - PubMed
- J Infect Dis. 2008 Feb 15;197(4):563-71 - PubMed
- J Infect Dis. 2005 Jul 1;192(1):46-55 - PubMed
- AIDS. 2007 May 11;21(8):1043-5 - PubMed
- AIDS. 1997 Dec;11(15):1833-8 - PubMed
- J Virol. 2012 Apr;86(7):4014-8 - PubMed
- J Virol. 2012 Jan;86(1):277-83 - PubMed
- J Immunol. 2010 May 1;184(9):4926-35 - PubMed
- Ann Intern Med. 1997 Jun 15;126(12):946-54 - PubMed
- AIDS. 2010 Jul 31;24(12):1917-22 - PubMed
- Nature. 2002 May 2;417(6884):95-8 - PubMed
- Ann Intern Med. 2001 Nov 6;135(9):782-95 - PubMed
- Clin Infect Dis. 2012 May;54(10):1495-503 - PubMed
- Nat Med. 1996 Nov;2(11):1240-3 - PubMed
- J Virol. 2008 Sep;82(17):8422-30 - PubMed
- PLoS One. 2008;3(12):e3907 - PubMed
- J Infect Dis. 1991 May;163(5):959-65 - PubMed
- J Immunol. 2002 Jun 1;168(11):5954-8 - PubMed
- J Infect Dis. 2001 Mar 1;183(5):736-43 - PubMed
- Trends Immunol. 2003 Dec;24(12):628-32 - PubMed
- J Infect Dis. 1999 Jul;180(1):68-75 - PubMed
- Science. 1995 Nov 10;270(5238):988-91 - PubMed
- PLoS Pathog. 2011 Feb;7(2):e1001300 - PubMed
- Immunol Today. 1998 Sep;19(9):395-404 - PubMed
- J Virol. 2010 Aug;84(15):7581-91 - PubMed
- Annu Rev Med. 2003;54:535-51 - PubMed
- Annu Rev Immunol. 2011;29:621-63 - PubMed
- Virology. 2002 Dec 20;304(2):246-64 - PubMed
- J Biol Chem. 1997 Dec 5;272(49):30603-6 - PubMed
- J Virol. 2004 Aug;78(16):8844-51 - PubMed
- J Virol. 2007 Dec;81(24):13904-15 - PubMed
- Retrovirology. 2008 Sep 22;5:84 - PubMed
- J Infect Dis. 1994 May;169(5):968-74 - PubMed
- AIDS Res Hum Retroviruses. 2012 Dec;28(12):1565-73 - PubMed
- J Acquir Immune Defic Syndr. 2006 Jun;42(2):192-202 - PubMed
- Proc Natl Acad Sci U S A. 2005 May 17;102(20):7239-44 - PubMed
- Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2709-14 - PubMed
- Immunity. 1999 Jun;10(6):661-71 - PubMed
- Nature. 1998 Jan 22;391(6665):397-401 - PubMed
- AIDS. 2002 May 3;16(7):961-72 - PubMed
- Science. 1996 Sep 27;273(5283):1856-62 - PubMed
- Annu Rev Immunol. 1999;17:625-56 - PubMed
- Retrovirology. 2013 Jan 07;10:1 - PubMed
- J Virol. 1997 Apr;71(4):3120-8 - PubMed
- Blood. 1998 Nov 1;92(9):3105-14 - PubMed
- Nat Med. 2007 Jan;13(1):46-53 - PubMed
- J Virol. 2007 Nov;81(22):12382-93 - PubMed
- J Infect Dis. 1999 Aug;180(2):320-9 - PubMed
- J Exp Med. 1998 Dec 21;188(12):2199-204 - PubMed
- J Immunol. 2012 Mar 1;188(5):2198-206 - PubMed
- Clin Dev Immunol. 2012;2012:153863 - PubMed
- J Virol. 2011 Mar;85(5):2316-24 - PubMed
- Nat Rev Immunol. 2010 Jan;10(1):11-23 - PubMed
- Nat Med. 2010 Oct;16(10):1147-51 - PubMed
- N Engl J Med. 2009 Oct 15;361(16):1548-59 - PubMed
- J Immunol. 2011 Jan 1;186(1):479-88 - PubMed
- Eur J Immunol. 2013 Feb;43(2):510-20 - PubMed
- J Clin Invest. 2012 Sep;122(9):3281-94 - PubMed
- Nature. 2010 May 20;465(7296):350-4 - PubMed
- J Virol. 2004 May;78(9):4463-77 - PubMed
- N Engl J Med. 1991 Apr 4;324(14):954-60 - PubMed
- J Virol. 2009 Sep;83(17):8616-27 - PubMed
- Science. 2010 Dec 10;330(6010):1551-7 - PubMed
- J Exp Med. 2007 Nov 26;204(12):2813-24 - PubMed
- Nat Med. 2009 Aug;15(8):893-900 - PubMed
- PLoS Pathog. 2009 Apr;5(4):e1000377 - PubMed
- J Clin Invest. 1989 Dec;84(6):1892-9 - PubMed
- J Infect Dis. 2007 Jun 15;195(12):1762-4 - PubMed
- J Acquir Immune Defic Syndr. 2008 Feb 1;47(2):140-47 - PubMed
- Nature. 2006 Sep 21;443(7109):350-4 - PubMed
- Nat Immunol. 2012 Jun 10;13(7):691-700 - PubMed
- Blood. 2009 Jul 9;114(2):346-56 - PubMed
- J Exp Med. 2009 Jun 8;206(6):1253-72 - PubMed
- J Virol. 2011 Jan;85(2):979-86 - PubMed
- Blood. 2011 Jul 28;118(4):955-64 - PubMed
- Clin Infect Dis. 2005 Oct 1;41(7):1053-6 - PubMed
- J Immunol. 2010 Jul 1;185(1):498-506 - PubMed
- J Infect Dis. 2011 Mar 15;203(6):803-9 - PubMed
- PLoS Pathog. 2012;8(3):e1002529 - PubMed
- J Virol. 2013 Apr;87(7):3760-73 - PubMed
- J Virol. 2006 Oct;80(20):10162-72 - PubMed
- J Exp Med. 2007 Nov 26;204(12):3027-36 - PubMed
- J Exp Med. 2012 Jul 30;209(8):1391-5 - PubMed
- J Infect Dis. 2005 May 1;191(9):1410-8 - PubMed
- Top HIV Med. 2007 Aug-Sep;15(4):134-6 - PubMed
- J Clin Invest. 1988 Dec;82(6):1908-14 - PubMed
- Blood. 2005 Sep 1;106(5):1660-7 - PubMed
- Science. 2007 Aug 17;317(5840):944-7 - PubMed
- Ann Intern Med. 1995 Apr 15;122(8):573-9 - PubMed
- Nat Immunol. 2002 Nov;3(11):1061-8 - PubMed
- J Virol. 2004 Jan;78(2):630-41 - PubMed
- PLoS Pathog. 2013 Mar;9(3):e1003211 - PubMed
- AIDS. 2010 Nov 13;24(17):2619-28 - PubMed
- Eur J Immunol. 1997 Dec;27(12):3223-7 - PubMed
- Nat Rev Microbiol. 2007 Feb;5(2):95-106 - PubMed
- J Exp Med. 2006 Dec 25;203(13):2865-77 - PubMed
- AIDS. 2003 Jan 24;17(2):264-7 - PubMed
- Semin Immunol. 2008 Jun;20(3):181-6 - PubMed
- Clin Infect Dis. 2009 Sep 15;49(6):982-6 - PubMed
- Nature. 1994 Jun 2;369(6479):403-7 - PubMed
- AIDS. 2004 Mar 26;18(5):749-55 - PubMed
- J Clin Invest. 2011 Apr;121(4):1549-60 - PubMed
- Nature. 2011 May 25;474(7353):654-7 - PubMed
- Science. 1997 Nov 21;278(5342):1447-50 - PubMed
- Retrovirology. 2008 Dec 11;5:112 - PubMed
- J Immunol. 2012 Apr 1;188(7):3247-56 - PubMed
- Eur J Immunol. 2001 Dec;31(12):3782-8 - PubMed
- J Exp Med. 2004 Sep 20;200(6):701-12 - PubMed
- Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16233-8 - PubMed
- Nat Immunol. 2012 Feb 12;13(3):223-228 - PubMed
- Cell. 1998 May 29;93(5):673-6 - PubMed
- Nature. 2010 Mar 11;464(7286):217-23 - PubMed
- Nat Med. 1997 Feb;3(2):212-7 - PubMed
- J Clin Invest. 2001 Feb;107(4):505-17 - PubMed
- Nat Rev Immunol. 2004 Aug;4(8):630-40 - PubMed
- Virology. 2010 Sep 15;405(1):81-92 - PubMed
- J Virol. 2011 Jan;85(2):733-41 - PubMed
- N Engl J Med. 1995 Jan 26;332(4):209-16 - PubMed
- J Immunol. 1999 Oct 15;163(8):4597-603 - PubMed
- Nat Med. 2002 May;8(5):493-9 - PubMed
- AIDS. 2011 Nov 13;25(17):2069-78 - PubMed
- J Exp Med. 2007 Oct 1;204(10):2473-85 - PubMed
- Nature. 2000 Sep 21;407(6802):386-90 - PubMed
- Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6776-81 - PubMed
- Nature. 2001 Jul 19;412(6844):334-8 - PubMed
- J Immunol. 2007 Mar 1;178(5):2746-54 - PubMed
- J Exp Med. 2001 Feb 5;193(3):375-86 - PubMed
- J Virol. 2012 Sep;86(18):9802-16 - PubMed
- Blood. 2006 Jun 15;107(12):4781-9 - PubMed
- J Infect Dis. 2010 Jan 15;201(2):272-84 - PubMed
- J Virol. 2010 Apr;84(7):3644-53 - PubMed
- Annu Rev Microbiol. 1996;50:825-54 - PubMed
- Nature. 2011 Jun 29;474(7353):658-61 - PubMed
- Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9791-6 - PubMed
- Nature. 2011 Nov 06;480(7377):379-82 - PubMed
- Science. 2010 Aug 13;329(5993):811-7 - PubMed
- PLoS Pathog. 2010 Feb 26;6(2):e1000780 - PubMed
- Retrovirology. 2007 Sep 23;4:66 - PubMed
- J Clin Invest. 2012 Sep;122(9):3271-80 - PubMed
- J Immunol. 2008 Oct 1;181(7):5137-46 - PubMed
- PLoS Pathog. 2008 Feb 8;4(2):e18 - PubMed
- J Immunol. 2011 Jan 1;186(1):359-71 - PubMed
- Annu Rev Immunol. 2004;22:745-63 - PubMed
- Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13878-83 - PubMed
- Nature. 2011 Apr 28;472(7344):495-8 - PubMed
- Blood. 2009 Jun 18;113(25):6351-60 - PubMed
- J Virol. 2007 Mar;81(5):2508-18 - PubMed
- Nature. 2011 Sep 22;477(7365):466-70 - PubMed
- AIDS. 1995 Jun;9(6):561-6 - PubMed
- J Virol. 1994 Jul;68(7):4650-5 - PubMed
- J Exp Med. 2001 Jan 15;193(2):181-94 - PubMed
- PLoS One. 2012;7(2):e29844 - PubMed
- J Infect Dis. 2009 Dec 1;200(11):1714-23 - PubMed
- Lancet. 1985 Mar 9;1(8428):537-40 - PubMed
- J Infect Dis. 1998 Mar;177(3):551-6 - PubMed
- Nat Immunol. 2007 Nov;8(11):1246-54 - PubMed
- Lancet. 1992 Oct 10;340(8824):863-7 - PubMed
- Clin Infect Dis. 2010 Jul 15;51(2):233-8 - PubMed
- AIDS. 2003 Dec 5;17(18):2581-91 - PubMed
- Science. 1986 Dec 19;234(4783):1563-6 - PubMed
- J Acquir Immune Defic Syndr. 2011 Oct 1;58(2):127-31 - PubMed
- Hum Immunol. 2004 May;65(5):486-92 - PubMed
Publication Types