HLA-B57/B*5801 human immunodeficiency virus type 1 elite controllers select for rare gag variants associated with reduced viral replication capacity and strong cytotoxic T-lymphocyte [corrected] recognition.

Human immunodeficiency virus type 1 (HIV-1) elite controllers (EC) maintain viremia below the limit of commercial assay detection (<50 RNA copies/ml) in the absence of antiviral therapy, but the mechanisms of control remain unclear. HLA-B57 and the closely related allele B*5801 are particularly associated with enhanced control and recognize the same Gag(240-249) TW10 epitope. The typical escape mutation (T242N) within this epitope diminishes viral replication capacity in chronically infected persons; however, little is known about TW10 epitope sequences in residual replicating viruses in B57/B*5801 EC and the extent to which mutations within this epitope may influence steady-state viremia. Here we analyzed TW10 in a total of 50 B57/B*5801-positive subjects (23 EC and 27 viremic subjects). Autologous plasma viral sequences from both EC and viremic subjects frequently harbored the typical cytotoxic T-lymphocyte (CTL)-selected mutation T242N (15/23 sequences [65.2%] versus 23/27 sequences [85.1%], respectively; P = 0.18). However, other unique mutants were identified in HIV controllers, both within and flanking TW10, that were associated with an even greater reduction in viral replication capacity in vitro. In addition, strong CTL responses to many of these unique TW10 variants were detected by gamma interferon-specific enzyme-linked immunospot assay. These data suggest a dual mechanism for durable control of HIV replication, consisting of viral fitness loss resulting from CTL escape mutations together with strong CD8 T-cell immune responses to the arising variant epitopes.

Pharmaceutical speakers' bureaus, academic freedom, and the management of promotional speaking at academic medical centers.

Pharmaceutical companies routinely engage physicians, particularly those with prestigious academic credentials, to deliver "educational" talks to groups of physicians in the community to help market the company's brand-name drugs. Although presented as educational, and even though they provide educational content, these events are intended to influence decisions about drug selection in ways that are not based on the suitability and effectiveness of the product, but on the prestige and persuasiveness of the speaker. A number of state legislatures and most academic medical centers have attempted to restrict physician participation in pharmaceutical marketing activities, though most restrictions are not absolute and have proven difficult to enforce. This article reviews the literature on why Speakers' Bureaus have become a lightning rod for academic/industry conflicts of interest and examines the arguments of those who defend physician participation. It considers whether the restrictions on Speakers' Bureaus are consistent with principles of academic freedom and concludes with the legal and institutional efforts to manage industry speaking.

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

A method for identification of HIV gp140 binding memory B cells in human blood.

Antibodies to HIV are potentially important reagents for basic and clinical studies. Historically, these reagents have been produced by random cloning of heavy and light chains in phage display libraries [Burton, D.R., Barbas, C.F. III, Persson, M.A.A., Koenig, S., Chanock, R.M., and Lerner, R.A., (1991), A large array of human monoclonal antibodies to type 1 immunodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals. Proc. Natl. Acad. Sci. U. S. A. 88, 10134-10137.] and electrofusion techniques [Buchacher, A., Predl, R., Tauer, C., Purtscher, M., Gruber, G., Heider, R., Steindl, F., Trkola, A., Jungbauer, A., and Katinger, H., (1992), Human monoclonal antibodies against gp41 and gp120 as potential agent for passive immunization. Vaccines 92, 191-195]. Here we describe a method to identify and potentially enrich human memory B cells from HIV infected patients that show serum titers of neutralizing antibodies. When biotinylated gp140 is used to stain peripheral blood mononuclear cells it identifies a distinct population of gp140 binding B cells by flow cytometry.

Persistent low-level viremia in HIV-1 elite controllers and relationship to immunologic parameters.

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) elite controllers are able to control virus replication to levels below the limits of detection by commercial assays, but the actual level of viremia in these individuals is not well defined. Here, we quantify plasma HIV-1 RNA in elite controllers and correlate this with specific immunologic parameters. METHODS: Plasma HIV-1 RNA levels were quantified in 90 elite controllers with use of a real time reverse-transcriptase polymerase chain reaction assay with a sensitivity of 0.2 copies/mL. HIV-1-specific immune responses and longitudinal CD4(+) T cell counts were examined. RESULTS: The median plasma HIV-1 RNA level was 2 copies/mL (interquartile range, 0.2-14 copies/mL). A longitudinal analysis of 31 elite controllers demonstrated 2-5-fold fluctuations in viremia in the majority of individuals; 6 had persistent levels below 1 copy/mL. Viremia correlated directly with HIV-1-specific neutralizing antibodies and Western blot reactivity but not with CD8(+) T cell responses. Absolute CD4(+) T cell decrease was more common among individuals with detectable viremia (P = .04). CONCLUSIONS: Low-level viremia is present in the majority of elite controllers and is associated with higher HIV-1-specific antibody responses. Absolute CD4(+) T cell loss is more common among viremic individuals, suggesting that even very low-level viremia has negative consequences over time.