Kaslow, R.A. et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat. Med. 2, 405-411
University of Alabama at Birmingham, School of Public Health, Department of Epidemiology, Birmingham, Alabama 35294, USA. Nature Medicine
(Impact Factor: 27.36).
Major histocompatibility complex (MHC) genes (HLA in humans) regulate the immune response to foreign antigens. Molecular and serologic techniques were used to identify products of HLA class I, class II and transporter (TAP) genes (also part of the MHC) in homosexual seroconverters to human immunodeficiency virus type 1 (HIV-1). Comprehensive statistical analysis produced an HLA profile that predicted time from HIV-1 infection to the onset of AIDS. The profile was developed in a cohort of 139 men and evaluated in a second unrelated cohort of 102 men. In the evaluation cohort, the profile discriminated a sixfold difference between groups with the shortest and longest times to AIDS (P = 0.001). These findings support current theory about control of antigen processing by HLA genes and have implications for immunopathogenesis of HIV-1 and other infections.
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- "B57, in LTNP/EC cohorts, such as, B15, B44, B51, B58 and B81 (Flores-Villanueva et al., 2001; Frahm et al., 2006; Goulder et al., 2000; Kaslow et al., 1996; Zhang et al., 2011). However, these same responses were also identified in progressors. "
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ABSTRACT: Understanding natural immunologic control over Human Immunodeficiency Virus (HIV)-1 replication, as occurs in rare long-term nonprogressors/elite controllers (LTNP/EC), should inform the design of efficacious HIV vaccines and immunotherapies. Durable control in LTNP/EC is likely mediated by highly functional virus-specific CD8+ T-cells. Protective Human Leukocyte Antigen (HLA) class I alleles, like B*27 and B*57, are present in most, but not all LTNP/EC, providing an opportunity to investigate features shared by their HIV-specific immune responses. To better understand the contribution of epitope targeting and conservation to immune control, we compared the CD8+ T-cell specificity and function of B*27/57neg LTNP/EC (n = 23), B*27/57pos LTNP/EC (n = 23) and B*27/57neg progressors (n = 13). Fine mapping revealed 11 previously unreported immunodominant responses. Although B*27/57neg LTNP/EC did not target more highly conserved epitopes, their CD8+ T-cell cytotoxic capacity was significantly higher than progressors. Similar to B*27/57pos LTNP/EC, this superior cytotoxicity was mediated by preferential expansion of immunodominant responses and lysis through the predicted HLA. These findings suggest that increased CD8+ T-cell cytotoxic capacity is a common mechanism of control in most LTNP/EC regardless of HLA type. They also suggest that potent cytotoxicity can be mediated through various epitopes and HLA molecules and could, in theory, be induced in most people.
Available from: Jean-Pierre Routy
- "The role of host genetics in HIV-1 infection continues to inform our understanding of HIV-1 pathogenesis. HLA-B*57 was first described as associated with a long-term non-progressive phenotype in chronic HIV-1 infection in 1996 , yet a clear understanding of how and why this allele contributes to the host response against viral replication still remains largely elusive. Previous studies including our own have implicated a role for HLA-B*57-restricted CD8+ T-cell responses in controlling viral replication [11,12]. "
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ABSTRACT: HLA-B alleles are associated with viral control in chronic HIV-1 infection, however, their role in primary HIV-1 disease is unclear. This study sought to determine the role of HLA-B alleles in viral control during the acute phase of HIV-1 infection and establishment of the early viral load set point (VLSP).
Individuals identified during primary HIV-1 infection were HLA class I typed and followed longitudinally. Associations between HLA-B alleles and HIV-1 viral replication during acute infection and VLSP were analyzed in untreated subjects. The results showed that neither HLA-B*57 nor HLA-B*27 were significantly associated with viral control during acute HIV-1 infection (Fiebig stage I-IV, n=171). HLA-B*57 was however significantly associated with a subsequent lower VLSP (p<0.001, n=135) with nearly 1 log10 less median viral load. Analysis of a known polymorphism at position 97 of HLA-B showed significant associations with both lower initial viral load (p<0.01) and lower VLSP (p<0.05). However, this association was dependent on different amino acids at this position for each endpoint.
The effect of HLA-B*57 on viral control is more pronounced during the later stages of primary HIV-1 infection, which suggests the underlying mechanism of control occurs at a critical period in the first several months after HIV-1 acquisition. The risk profile of polymorphisms at position 97 of HLA-B are more broadly associated with HIV-1 viral load during primary infection and may serve as a focal point in further studies of HLA-B function.
Available from: Lauren J. MacKenzie
- "While the factors influencing these trends are undoubtedly complex and multi-factorial, they may not be entirely attributable to social and structural factors. For over a decade, research has linked the human leukocyte antigen (HLA) class I alleles as having both protective (HLA B27, B51, B5701) and harmful (HLA B35) effects in HIV disease progression (Brumme et al., 2007; Carrington and O'Brien, 2003; International HIV Controllers Study, 2010; Kaslow et al., 1996; Pelak et al., 2010, Smeraldi et al., 1986). The enrichment of HLA alleles predisposing to rapid disease progression, together with the rarity of the protective HLA alleles among individuals of Aboriginal descent may be a contributing factor to a more rapid disease progression, as evidenced by the degree of immune suppression seen at presentation among the persons in care within the HIV clinics in Manitoba. "
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ABSTRACT: Within Manitoba, Aboriginal people make up 15% of the province’s population, but accounted for 53% of new human immunodeficiency virus (HIV) diagnoses in 2011. For over a decade, research has linked the human leukocyte antigen (HLA) class I alleles as having both protective and harmful effects in HIV disease progression. The abundance of HLA alleles that predispose to rapid disease progression, together with the rarity of protective HLA allele types, may be a contributing factor to a more rapid disease progression amongst individuals of Aboriginal ethnicity. We completed an epidemiological study on all HIV patients new to care in the Manitoba HIV Program in 2010, looking at markers of disease severity, such as CD4 cell count, rates of opportunistic infections (OI), and HLA type. In this cohort, the Aboriginal population was overrepresented, and presented with significantly more advanced HIV infection (lower CD4 counts, higher rates of OI), compared to patients from a Caucasian background. Our data supports previously identified associations between HLA type and disease progression, and demonstrates a difference in distribution of HLA type by ethnicity.
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