title: Virological and immunological factors associated with HIV-1 differential disease progression in HLA-B 58:01-positive individuals.
abstract: Molecular epidemiology studies have identified HLA-B 58:01 as a protective HIV allele. However, not all B 58:01-expressing persons exhibit slow HIV disease progression. We followed six HLA-B 58:01-positive, HIV subtype C-infected individuals for up to 31 months from the onset of infection and observed substantial variability in their clinical progression despite comparable total breadths of T cell responses. We therefore investigated additional immunological and virological factors that could explain their different disease trajectories. Cytotoxic T-lymphocyte (CTL) responses during acute infection predominantly targeted the TW10 and KF9 epitopes in p24(Gag) and Nef, respectively. Failure to target the TW10 epitope in one B 58:01-positive individual was associated with low CD4(+) counts and rapid disease progression. Among those targeting TW10, escape mutations arose within 2 to 15 weeks of infection. Rapid escape was associated with preexisting compensatory mutations in the transmitted viruses, which were present at a high frequency (69%) in the study population. At 1 year postinfection, B 58:01-positive individuals who targeted and developed escape mutations in the TW10 epitope (n = 5) retained significantly higher CD4(+) counts (P = 0.04), but not lower viral loads, than non-B 58:01-positive individuals (n = 17). The high population-level frequency of these compensatory mutations may be limiting the protective effect of the B 58:01 allele.
authors: Institute of Infectious Diseases and Molecular Medicine, Division of Medical Virology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors: D R
authors: DR
authors: Chopera
authors: M
authors: M
authors: Mlotshwa
authors: Z
authors: Z
authors: Woodman
authors: K
authors: K
authors: Mlisana
authors: D
authors: D
authors: de Assis Rosa
authors: D P
authors: DP
authors: Martin
authors: S
authors: S
authors: Abdool Karim
authors: C M
authors: CM
authors: Gray
authors: C
authors: C
authors: Williamson
references: AIDS Res Hum Retroviruses. 1996 Dec 10;12(18):1691-8
references: 8959245
references: Ann Intern Med. 1997 Jun 15;126(12):946-54
references: 9182471
references: Nature. 2004 Dec 9;432(7018):769-75
references: 15592417
references: J Virol. 2011 Apr;85(7):3128-41
references: 21270156
references: Nat Med. 2007 Jan;13(1):46-53
references: 17173051
references: Science. 1999 Mar 12;283(5408):1748-52
references: 10073943
references: PLoS Comput Biol. 2008 Feb 29;4(2):e1000016
references: 18392148
references: J Immunol. 2004 Oct 1;173(7):4607-17
references: 15383595
references: AIDS Res Hum Retroviruses. 2011 Nov;27(11):1167-72
references: 21198409
references: Trends Mol Med. 2001 Sep;7(9):379-81
references: 11530315
references: PLoS One. 2008 Apr 16;3(4):e1954
references: 18414658
references: N Engl J Med. 1990 Jan 18;322(3):166-72
references: 1967191
references: Nat Rev Immunol. 2004 Aug;4(8):630-40
references: 15286729
references: J Virol. 2010 May;84(9):4461-8
references: 20147397
references: Nucleic Acids Res. 1994 Nov 11;22(22):4673-80
references: 7984417
references: J Virol. 2007 Aug;81(15):8346-51
references: 17507468
references: Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12266-70
references: 15302942
references: J Virol. 2008 Sep;82(18):9216-27
references: 18614631
references: AIDS. 2010 Jul 31;24(12):1835-40
references: 20588164
references: J Virol. 2009 Mar;83(6):2743-55
references: 19116253
references: PLoS Pathog. 2008 Mar 21;4(3):e1000033
references: 18369479
references: J Virol. 2007 Nov;81(22):12608-18
references: 17728232
references: J Exp Med. 2009 Apr 13;206(4):909-21
references: 19307327
references: JAMA. 2006 Sep 27;296(12):1498-506
references: 17003398
references: Nat Med. 2004 Mar;10(3):282-9
references: 14770175
references: J Virol. 2009 Sep;83(17):8616-27
references: 19515764
references: J Virol. 2009 Jan;83(1):470-8
references: 18945774
references: AIDS Res Hum Retroviruses. 1997 Jun 10;13(9):737-42
references: 9171217
references: PLoS Med. 2006 Oct;3(10):e403
references: 17076553
references: J Virol. 2009 Mar;83(6):2460-8
references: 19109381
references: J Virol. 2006 Apr;80(7):3617-23
references: 16537629
references: J Exp Med. 2008 May 12;205(5):1009-17
references: 18426987
references: AIDS. 2003 Dec 5;17(18):2581-91
references: 14685052