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There are over 40 million people living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) worldwide. In 2005, there were five million new infections and three million deaths. With greater than 95% of infections occurring in countries unable to afford antiretroviral therapy, the development of a prophylactic HIV vaccine remains one of the world's top public health priorities. The failure of previous vaccines has increased the need for novel approaches in addressing this problem. Many studies illustrate the important role of CD8+ T lymphocytes in controlling HIV and simian immunodeficiency virus (SIV) replication. However, the correlates of immune protection remain unknown. We approached this issue by first defining the breadth of CD8 + responses in the SIV-infected macaque model and then investigating the antiviral efficacy of these CD8+ T lymphocytes. Using major histocompatibility complex (MHC) class I-defined, SIV-infected Indian rhesus macaques (Macaca mulatta) as an animal model for HIV infection, we identified novel CD8+ T lymphocyte epitopes restricted by the MHC class I molecules Mamu-A*02 and Mamu-A*11. The CD8+ T lymphocyte epitopes have been instrumental in understanding the breadth of the CD8+ T lymphocyte responses in vaccinated and SIV-infected macaques. Next, we examined the types of antigen-specific CD8+ T lymphocyte responses that were effective at suppressing SIV replication using a novel viral suppression assay. Recent studies in HIV-infected humans suggested differences in antiviral efficacy between CD8+ T lymphocytes directed against early versus late viral proteins. We initially hypothesized that antigen-specific CD8+ T lymphocytes directed against early proteins would be more effective in suppressing viral replication than CD8+ T lymphocytes directed against proteins expressed later in the viral replication cycle. However, our results suggested that not all CD8+ T lymphocytes responses directed against early proteins are effective at suppressing SIV replication. We also found that a variety of factors likely contribute to the ability of CD8+ T lymphocytes to suppress viral replication including functional avidity, viral escape, epitope location, and disease progression of the animal. This information may be important in determining the CD8+ T cell epitopes to be targeted by vaccination in future HIV studies.

The epidemic of type 2 diabetes mellitus (T2DM) is an important global health concern. Our earlier epidemiological investigation in Pakistan prompted us to conduct a molecular investigation to decipher the differential genetic pathways of this health condition in relation to non-diabetic controls. Our microarray studies of global gene expression were conducted on the Affymetrix platform using Human Genome U133 Plus 2.0 Array along with Ingenuity Pathway Analysis (IPA) to associate the affected genes with their canonical pathways. High-throughput qRT-PCR TaqMan Low Density Array (TLDA) was performed to validate the selected differentially expressed genes of our interest, viz., ARNT, LEPR, MYC, RRAD, CYP2D6, TP53, APOC1, APOC2, CYP1B1, SLC2A13, and SLC33A1 using a small population validation sample (n = 15 cases and their corresponding matched controls). Overall, our small pilot study revealed a discrete gene expression profile in cases compared to controls. The disease pathways included: Insulin Receptor Signaling, Type II Diabetes Mellitus Signaling, Apoptosis Signaling, Aryl Hydrocarbon Receptor Signaling, p53 Signaling, Mitochondrial Dysfunction, Chronic Myeloid Leukemia Signaling, Parkinson’s Signaling, Molecular Mechanism of Cancer, and Cell Cycle G1/S Checkpoint Regulation, GABA Receptor Signaling, Neuroinflammation Signaling Pathway, Dopamine Receptor Signaling, Sirtuin Signaling Pathway, Oxidative Phosphorylation, LXR/RXR Activation, and Mitochondrial Dysfunction, strongly consistent with the evidence from epidemiological studies. These gene fingerprints could lead to the development of biomarkers for the identification of subgroups at high risk for future disease well ahead of time, before the actual disease becomes visible.

The goal of the present study was to develop a nonhuman primate model of intravaginal human immunodeficiency virus (HIV) transmission with cell-associated virus. Reproductively mature, cycling cynomolgus macaques with or without chemically induced, transient ulcers of the lower female reproductive tract repeatedly received challenge with a variable amount of in vitro simian immunodeficiency virus mac239–infected peripheral blood mononuclear cells. Persistent viremia was established with surprisingly few infectious lymphocytes containing physiologically relevant quantities of cell-associated virus. This model will be indispensable for the testing of vaccines and topical agents that are aimed toward the prevention of heterosexual transmission of HIV

It is generally accepted that CD8+ T cell responses play an important role in control of immunodeficiency virus replication. The association of HLA-B27 and -B57 with control of viremia supports this conclusion. However, specific correlates of viral control in individuals expressing these alleles have been difficult to define. We recently reported that transient in vivo CD8+ cell depletion in simian immunodeficiency virus (SIV)-infected elite controller (EC) macaques resulted in a brief period of viral recrudescence. SIV replication was rapidly controlled with the reappearance of CD8+ cells, implicating that these cells actively suppress viral replication in ECs. Here we show that three ECs in that study made at least seven robust CD8+ T cell responses directed against novel epitopes in Vif, Rev, and Nef restricted by the MHC class I molecule Mamu-B*08. Two of these Mamu-B*08-positive animals subsequently lost control of SIV replication. Their breakthrough virus harbored substitutions in multiple Mamu-B*08-restricted epitopes. Indeed, we found evidence for selection pressure mediated by Mamu-B*08-restricted CD8+ T cells in all of the newly identified epitopes in a cohort of chronically infected macaques. Together, our data suggest that Mamu-B*08-restricted CD8+ T cell responses effectively control replication of pathogenic SIV(mac)239. All seven regions encoding Mamu-B*08-restricted CD8+ T cell epitopes also exhibit amino acid replacements typically seen only in the presence of Mamu-B*08, suggesting that the variation we observe is indeed selected by CD8+ T cell responses. SIV(mac)239 infection of Indian rhesus macaques expressing Mamu-B*08 may therefore provide an animal model for understanding CD8+ T cell-mediated control of HIV replication in humans.

It is generally accepted that CD8.sup.+ T cell responses play an important role in control of immunodeficiency virus replication. The association of HLA-B27 and -B57 with control of viremia supports this conclusion. However, specific correlates of viral control in individuals expressing these alleles have been difficult to define. We recently reported that transient in vivo CD8.sup.+ cell depletion in simian immunodeficiency virus (SIV)-infected elite controller (EC) macaques resulted in a brief period of viral recrudescence. SIV replication was rapidly controlled with the reappearance of CD8.sup.+ cells, implicating that these cells actively suppress viral replication in ECs. Here we show that three ECs in that study made at least seven robust CD8.sup.+ T cell responses directed against novel epitopes in Vif, Rev, and Nef restricted by the MHC class I molecule Mamu-B*08. Two of these Mamu-B*08-positive animals subsequently lost control of SIV replication. Their breakthrough virus harbored substitutions in multiple Mamu-B*08-restricted epitopes. Indeed, we found evidence for selection pressure mediated by Mamu-B*08-restricted CD8.sup.+ T cells in all of the newly identified epitopes in a cohort of chronically infected macaques. Together, our data suggest that Mamu-B*08-restricted CD8.sup.+ T cell responses effectively control replication of pathogenic SIV.sub.mac 239. All seven regions encoding Mamu-B*08-restricted CD8.sup.+ T cell epitopes also exhibit amino acid replacements typically seen only in the presence of Mamu-B*08, suggesting that the variation we observe is indeed selected by CD8.sup.+ T cell responses. SIV.sub.mac 239 infection of Indian rhesus macaques expressing Mamu-B*08 may therefore provide an animal model for understanding CD8.sup.+ T cell-mediated control of HIV replication in humans.

Characterization of ancestry-linked peptide variants in disease-relevant patient tissues represents a foundational step to connect patient ancestry with molecular disease pathogenesis. Nonsynonymous single nucleotide polymorphisms (SNPs) encoding missense substitutions within tryptic peptides exhibiting high allele frequencies in European, African, and East Asian populations, termed peptide ancestry informative markers (pAIMs), were prioritized from 1000 genomes. In silico analysis shows that as few as 20 pAIMs can determine ancestry proportions similarly to >260K SNPs (R2=0.9905). Multiplexed proteomic analysis of >100 human endometrial cancer cell lines and uterine leiomyoma tissues resulted in the quantitation of 62 pAIMs that correlate with self-described race and genotype-confirmed patient ancestry. Candidates include a D451E substitution in GC vitamin D-binding protein previously associated with altered vitamin D levels in African and European populations. These efforts describe a generalized set of markers for proteoancestry assessment that will further support studies investigating the impact of ancestry on the human proteome and how this relates to the pathogenesis of uterine neoplasms. Competing Interest Statement GLM is a consultant for Kiyatec, GSK, and Merck. TPC is a ThermoFisher Scientific, Inc SAB member and receives research funding from AbbVie. GJP has received a patent based on concepts presented in this study, (US 8,877,455 B2, Australian Patent 2011229918, Canadian Patent CA 2794248, and European Patent EP11759843.3).