Impact of MHC class I diversity on immune control of immunodeficiency virus replication

Abstract

The recent failure of the T-cell-based HIV vaccine trial led by Merck & Co., Inc. prompts the urgent need to refocus on the question of which T-cell responses are required to control HIV replication. The well-described association between the expression of particular MHC class I molecules and successful containment of HIV or, in the macaque model, SIV replication provide a valuable starting point from which to evaluate more precisely what might constitute effective CD8 + T-cell responses. Here, we review recent studies of T-cell-mediated control of HIV and SIV infection, and offer insight for the design of a successful T-cell-based HIV vaccine in the future.The HIV epidemic continues unabated. In 2007, there were an estimated 2.5 million new reported cases of infection and 2.1 million HIV-related deaths (see the UNAIDS WHO AIDS epidemic update). This brings the estimated total number of people who have been infected with HIV since 1981 to 58 million, of whom 25 million have died. Although antiretroviral therapy has, since the mid-1990s, transformed the management and prognosis of HIV infection in resource-rich countries, only a small fraction -approximately a quarter (see the AVERT website) -of HIV-infected people in resource-poor countries have access to needed antiretroviral therapy. The demand for an effective HIV vaccine has never been more urgent, and yet in 2007, the first advanced trials of a T-cell-based vaccine were abruptly halted because of lack of efficacy 1 . So, it is an opportune moment to reflect on what is currently known about the immune responses that can successfully control HIV replication, the extent to which data from studies of non-human primates infected with simian immunodeficiency virus (SIV) can This Review focuses on the central role of MHC class I alleles in the control of immunodeficiency virus replication. It is striking that, in a recent whole-genome association study of key determinants for host control of HIV-1, the six most highly significant protective determinants were within the MHC region 2 . We review the central role of CD8 + T cells in the control of HIV and SIV replication, the evidence that the impact of MHC molecules on HIV and SIV disease is substantially mediated by the particular epitope peptides presented by different MHC class I molecules, and describe the pre-eminent role of MHC-B alleles and CD8 + T-cell activity directed against the viral protein Gag in the control of HIV and SIV replication. We examine aspects of the effectiveness or dysfunctional nature of CD8 + T-cell activity in HIV infection that are unrelated or indirectly related to specificity of the response. Finally, we address the question of whether HIV is able to adapt to HLA alleles that are currently associated with control of the virus, and the prospects for a successful T-cell-based vaccine against HIV in the future. Role of CD8 + T cells in control of HIV replicationDuring acute HIV infection in adults, the increase in viraemia to a peak of ~10 7 HIV RNA copies per ml of plasma 3 is ...

AIDS-protective HLA-B*27/B*57 and chimpanzee MHC class I molecules target analogous conserved areas of HIV-1/SIVcpz

“…The peptide-binding motifs allowed us to scan the entire Gag protein for potential epitopes using a database (26). We paid particular attention to those areas of Gag that are also recognized by HLA-B*27/B*57, as these epitopes may be crucial for the control of viral replication in humans (19,27). These CTL epitopes have been designated IW9, KF11, TW10, KK10, and QW9 (Fig.…”

“…Immunodominant CTL responses to Gag found in HLA-B*27/ B*57-positive human long-term nonprogressors and HIV-1-infected chimpanzees may play a crucial role in the control of viral replication (19,27,30). The Gag protein may represent one of the Achilles' heels of HIV-1/SIV cpz .…”

“…The Gag protein may represent one of the Achilles' heels of HIV-1/SIV cpz . However, from a mechanistic point of view, it is not clearly understood how this works (27), because not all HLA-B*27-or -B*57-positive individuals can control an HIV-1 infection. Although heterozygous advantage may have an additional impact, other host and viral factors may play a role as well.…”

Activated CD4 + CCR5 + T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques

“…Key progress in this direction derived from a number of studies showing that several components of the host antiviral immune response, including CD8 + T-cell-mediated cytotoxic T-lymphocyte (CTL) responses, CD4 + T-cell responses, and neutralizing antibodies, have the potential to prevent or suppress HIV or Simian immunodeficiency virus (SIV) replication effectively in vivo (1)(2)(3)(4)(5)(6)(7)(8)(9). However, the development of an AIDS vaccine revealed remarkable scientific challenges that are related to specific aspects of HIV biology.…”

CTL recognition of HIV‐1‐infected cells via cross‐recognition of multiple overlapping peptides from a single 11‐mer Pol sequence

“…Cross-recognition r CTL r HIV r Peptides r T cells Supporting Information available online Introduction CD8 + T cells play important roles in controlling HIV-1 [1][2][3][4][5][6][7][8][9][10]. HIV-1-specific CD8 + T cells recognize peptides derived from HIV-1 proteins presented by HLA class I molecules on HIV-1-infected cells, and effectively although not completely control the replication of HIV-1 [1,5,11,12].…”