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Without therapy, most people infected with human immunodeficiency virus (HIV) ultimately progress to AIDS. Rare individuals ('elite controllers') maintain very low levels of HIV RNA without therapy, thereby making disease progression and transmission unlikely. Certain HLA class I alleles are markedly enriched in elite controllers, with the highest association observed for HLA-B57 (ref. 1). Because HLA molecules present viral peptides that activate CD8(+) T cells, an immune-mediated mechanism is probably responsible for superior control of HIV. Here we describe how the peptide-binding characteristics of HLA-B57 molecules affect thymic development such that, compared to other HLA-restricted T cells, a larger fraction of the naive repertoire of B57-restricted clones recognizes a viral epitope, and these T cells are more cross-reactive to mutants of targeted epitopes. Our calculations predict that such a T-cell repertoire imposes strong immune pressure on immunodominant HIV epitopes and emergent mutants, thereby promoting efficient control of the virus. Supporting these predictions, in a large cohort of HLA-typed individuals, our experiments show that the relative ability of HLA-B alleles to control HIV correlates with their peptide-binding characteristics that affect thymic development. Our results provide a conceptual framework that unifies diverse empirical observations, and have implications for vaccination strategies.

Natural killer (NK) cells have an important role in the control of viral infections, recognizing virally infected cells through a variety of activating and inhibitory receptors (1-3). Epidemiological and functional studies have recently suggested that NK cells can also contribute to the control of HIV-1 infection through recognition of virally infected cells by both activating and inhibitory killer immunoglobulin-like receptors (KIRs) (4-7). However, it remains unknown whether NK cells can directly mediate antiviral immune pressure in vivo in humans. Here we describe KIR-associated amino-acid polymorphisms in the HIV-1 sequence of chronically infected individuals, on a population level. We show that these KIR-associated HIV-1 sequence polymorphisms can enhance the binding of inhibitory KIRs to HIV-1-infected [CD4.sup.+] T cells, and reduce the antiviral activity of KIR-positive NK cells. These data demonstrate that KIR-positive NK cells can place immunological pressure on HIV-1, and that the virus can evade such NK-cell-mediated immune pressure by selecting for sequence polymorphisms, as was previously described for virus-specific T cells and neutralizing antibodies (8). NK cells might therefore have a previously underappreciated role in contributing to viral evolution., We hypothesized that HIV-1 can evade recognition by NK cells through the selection of sequence polymorphisms in regions targeted by KIRs, and that KIR-associated polymorphisms in the HIV-1 sequence can [...]

Author(s): Marcus Altfeld [1, 2]; Todd M. Allen [1, 2]; Xu G. Yu [1]; Mary N. Johnston [1]; Deepak Agrawal [1]; Bette T. Korber [3]; David C. Montefiori [4]; David [...]

Author(s): Todd M. Allen [1, 2]; David H. O'Connor [1, 2]; Peicheng Jing [1]; John L. Dzuris [3]; Bianca R. Mothé [1]; Thorsten U. Vogel [1]; Ed Dunphy [1]; Max [...]

Author(s): Marcus Altfeld; Todd M. Allen; Xu G. Yu; Mary N. Johnston; Deepak Agrawal; Bette T. Korber; David C. Montefiori; David H. O'Connor; Ben T. Davis; Paul K. Lee; Erica [...]

Early treatment of acute HIV-1 infection followed by treatment interruptions has shown promise for enhancing immune control of infection. A subsequent loss of control, however, allows the correlates of protective immunity to be assessed. Here we show that sudden breakthrough of plasma viraemia occurred after prolonged immune containment in an individual infected with HIV-1 at a time when 25 distinct CD8[sup +] T-cell epitopes in the viral proteins Gag, RT, Integrase, Env, Nef, Vpr, Vif and Rev were being targeted. Sequencing of the virus in plasma and cells showed that superinfection with a second clade-B virus was coincident with the loss of immune control. This sudden increase in viraemia was associated with a decline in half of the CD8[sup +] T-cell responses. The declining CD8[sup +] T-cell responses were coupled with sequence changes relative to the initial virus that resulted in impaired recognition. Our data show that HIV-1 superinfection can occur in the setting of a strong and broadly directed virus-specific CD8[sup +] T-cell response. The lack of cross-protective immunity for closely related HIV-1 strains, despite persistent recognition of multiple CD8 epitopes, has important implications for public health and vaccine development. [ABSTRACT FROM AUTHOR]

Presents additional information on the article 'HIV-1 superinfection despite broad CD8[sup+] T-cell responses containing replication of the primary virus,' published in the May 2003 issue of the journal 'Nature.'