Acquired Immunodeficiency Syndrome: Lu Y

Shao Y, Lu Y. · National Center for AIDS Prevention and Control, Beijing, P.R. China. · Crit Rev Oncog. · Pubmed #10327209 No free full text.

Abstract: Since 1984, studies from almost every branch of modern biology have filled in many gaps in our knowledge of human immunodeficiency virus type 1 (HIV-1). This review focuses on studies of biodiversity and bioseparation of HIV-1 envelope glycoproteins from the vaccine development point of view. It presents an updated picture of different systems for producing either native or recombinant HIV-1 envelope glycoproteins for the preparation of vaccine candidates. The prevention of HIV-1-associated disease is highly relevant to the abrogation of the neoplastic processes associated with this pathogen.

Lu Y. · University of Hawaii, Public Health Sciences, Honolulu, HI 96822, USA. · Methods Mol Biol. · Pubmed #19378133 No free full text.

Abstract: Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS). HIV-1 can infect human brain macrophages and microglial cells, causing HIV-associated dementia, or neuroAIDS, an increasingly common disorder of the central nervous system (CNS) that affects 20% of HIV-1-infected individuals. Current treatments for neuroAIDS are hampered by the poor efficiency of many antiretroviral drugs to cross the blood-brain barrier (BBB). Circulating blood monocytes and their derived macrophages are known to migrate across the BBB and enter the CNS under normal physiologic conditions and certain circumstances; some of these cells can subsequently mature into long-lived tissue-resident brain macrophages and microglia. Thus, the natural homing/migratory properties of blood monocyte-derived macrophages (MDM) can be potentially utilized as an effective genetic tool for delivering anti-HIV-1 genes to the CNS in a noninvasive and nonsurgical manner. To test and establish this macrophage-based gene therapy for the CNS, we have constructed and generated high-titered defective lentiviral vectors (DLV) expressing enhanced green fluorescent protein (GFP) as a reporter and optimized protocols for the isolation and long-term cultivation of primary MDM from humans and mice. We have demonstrated that primary cultures of human and mouse MDM can be efficiently modified in vitro using GFP-DLV vectors without apparently adverse effects on cellular biological properties. We have also shown that primary mouse MDM can enter the brain. The efficiency of CNS uptake of these cells can be enhanced through the use of bradykinin or a hypertonic mannitol solution for transient disruption of the BBB. These experimental methods and findings lay the initial groundwork for future in vivo studies on the ability of GFP-DLV-modified blood MDM to introduce anti-HIV-1 and neuroprotective genes into the CNS.

Lu Y, Robinson M, Zhang FJ. · Department of Public Health, Lanzhou University, Gansu, China. · Chin Med J (Engl). · Pubmed #19187624 links to  free full text

This publication has no abstract.

Zhai S, Zhuang Y, Song Y, Li S, Huang D, Kang W, Li X, Liao Q, Liu Y, Zhao Z, Lu Y, Sun Y. · Department of Infectious Diseases, Tangdu Hospital Affiliated to the Fourth Military Medical University, Xi'an, P.R. China. · Curr HIV Res. · Pubmed #18691032 No free full text.

Abstract: To assess the immunodominance patterns of HIV-1-specific cytotoxic T lymphocyte (CTL) responses and the contribution of these responses against the peptides scanning optimal epitopes in chronic infection, we test the HIV-1-specific CTL responses against a panel of 413 overlapping peptides spanning HIV-1 Asian B sequence, including 147 peptides corresponding to optimal clade B epitopes in 49 chronically HIV-1 infected individuals by interferon-gamma Elispot assay. A large variation in the recognition of peptides restricted by the same HLA class I allele is presented. Some epitopes are targeted frequently by individuals while other epitopes restricted by the same allele are rarely recognized in our research. HLA-B35 and HLA-A03 rather than other HLA alleles contribute greatly to total virus-specific CTL responses. Furthermore, there is a significant inverse correlation between the total contribution of HIV-1-specific CTL responses restricted by different HLA alleles to virus-specific immune responses and viral load in the individuals during advanced infection (P=0.002, r=-0.549). The peptides targeted by individuals have significantly lower entropy compared with those not targeted but restricted by the same HLA class I alleles (P<0.05) in 49 individuals infected by HIV-1, especially the advanced infection subgroup (P=0.044). These data demonstrate that the consistent immunodominance patterns of HIV-1-specific CTL responses of Chinese HIV-1 infected individuals and an inverse correlation between the relative contribution of responses restricted by HLA alleles and viral load, which indicates the important protective effect of optimal epitopes against slow disease progression even in advanced infection.

Waterman PM, Kitabwalla M, Hatfield GS, Evans PS, Lu Y, Tikhonov I, Bryant JL, Pauza CD. · Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, Maryland, USA. · Viral Immunol. · Pubmed #15671751 No free full text.

Abstract: HIV-1 vaccine candidates are designed to elicit Type 1 immune responses, including cytotoxic T cells and neutralizing antibodies. The type of immune response is influenced by many factors, including the levels of antigen expression and production of cytokines or chemokines; we designed a nonhuman primate study to evaluate the influence of these factors on protective immunity. Recombinant SHIV were engineered to express macrophage inflammatory protein-1 alpha (MIP-1alpha), regulated upon activation, normal T-cell expressed and secreted (RANTES), or Lymphotactin (Ltn) in place of nef in SHIV(89.6) (SHIV(89.6-MIP-1), SHIV(89.6-RANTES), SHIV(89.6-Ltn)). The parental virus SHIV(89.6) was included because it replicates to higher titer while still not causing disease. Control groups included animals that received a recombinant SHIV with a truncated chemokine construct (SHIV(89.6-dLtn)) and unvaccinated macaques. After pathogenic challenge with SHIV(89.6pd), animals from groups that received recombinant (nef-deleted) viruses had peak viremia levels three orders of magnitude lower than unvaccinated controls and increased survival times. Animals that received the original SHIV(89.6) (nef+) were highly resistant to both intrarectal and intravenous challenge with SHIV(89.6PD), and showed no signs of disease. There were no differences in survival times comparing unvaccinated and SHIV(89.6-dLtn) (control) groups, indicating that nef deleted viruses did not provide durable protection in this model. Strongest protection was seen in animals with the highest replicating virus (SHIV(89.6)), and the lower effect on survival after SHIV(89.6) nef-deleted vaccination, likely reflects differences in replication capacity. The protective effect of nef-deleted virus was partly restored by expressing Type 1 chemokines to augment viral immunity.

Wu X, Lu Y, He F, Qing C, Song H, Cong Z, Tong W. · Department of Virology and Pathology, Institute of Laboratory Animal Sciences, CAMS, PUMC, Beijing 100021, China. · Zhongguo Yi Xue Ke Xue Yuan Xue Bao. · Pubmed #12903498 No free full text.

Abstract: OBJECTIVE: To observe the characteristic immunodeficiency syndrome of the rapid fatal type of simian immunodeficiency virus (SIV) infected monkeys. METHODS: Eighty rhesus monkeys and 4 cynomolgus monkeys were intravenously inoculated with SIVmac or SIVmac251. The virus isolation and viral titer, estimation by indirect immunofluroresence and viral antibody were determined periodically from monkeys' plasma; lymph node biopsies were performed for pathohistological examination. RESULTS: Twelve out of 84 macaque (14.2%) died of rapid progressive type after inoculation of SIVmac and SIVmac251 in the duration 3 to 4 months. Dying monkeys showed persistent high viremia and low level titre antibody. Eight of 10 pathohistological changes showed severe depletion of lymphoid tissue in spleen and lymph nodes, there were remarkable immunodeficiency with opportunity infection. The other two monkeys appeared moderate lymphoid tissue deletion and hyperplasia without opportunity infections. The survived monkeys' (72/84) lymph nodes biopsies revealed hypoplasia of lymphoid tissue. CONCLUSIONS: The characteristic immunodeficiency syndrome of rapid fatal type of simian immunodeficiency virus infected monkeys could be made with persistent high viremia, low level antibody, severe lymphoid tissue deletion in lymph nodes and spleen, as well as complicated opportunity infections.

Lu W, Wu X, Lu Y, Guo W, Andrieu JM. · Institut de Recherche sur les Vaccins et l'Immunothérapie des Cancers et du Sida, Paris, France. · Nat Med. · Pubmed #12496959 No free full text.

Abstract: An effective immune response against human immunodeficiency virus or simian immunodeficiency virus (SIV) is critical in achieving control of viral replication. Here, we show in SIV-infected rhesus monkeys that an effective and durable SIV-specific cellular and humoral immunity is elicited by a vaccination with chemically inactivated SIV-pulsed dendritic cells. After three immunizations made at two-week intervals, the animals exhibited a 50-fold decrease of SIV DNA and a 1,000-fold decrease of SIV RNA in peripheral blood. Such reduced viral load levels were maintained over the remaining 34 weeks of the study. Molecular and cellular analyses of axillary and inguinal node lymphocytes of vaccinated monkeys revealed a correlation between decreased SIV DNA and RNA levels and increased SIV-specific T-cell responses. Neutralizing antibody responses were augmented and remained elevated. Inactivated whole virus-pulsed dendritic cell vaccines are promising means to control diseases caused by immuno- deficiency viruses.

Lu Y, Ding J, Chen YH. · Research Center for Medical Science and Department of Biology, Tsinghua University, Ministry of Education, Beijing, PR China. · Immunopharmacol Immunotoxicol. · Pubmed #11792008 No free full text.

Abstract: The failure of some candidate HIV-1 vaccines may result from inducing very weak neutralization activity against representative primary viral isolates. Based on our hypothesis that epitope-vaccine may be a new strategy to induce high levels of neutralizing antibodies against HIV-1, we designed two candidate multi-epitope-vaccines, EP1 [C-G-(ELDKWA-GPGRAFY)2-K] and EP2 (CG-GPGRAFY-G-ELDKWA-G-RILAVERYLKD), containing three neutralizing epitopes (GPGRAFY, ELDKWA and RILAVERYLKD) on HIV-1 envelope protein, and expected them to induce epitope-specific antibodies of predefined epitope-specificity. The two peptides were conjugated to carrier protein bovine serum albumin (BSA) and used for immunization of rabbits. Proteins were purified from the rabbit sera induced by both candidate multi-epitope-vaccines (EP1-BSA and EP2-BSA) through affinity chromatography with epitope-peptide-conjugated sepharose-column, and identified as antibodies in silver-staining and immunoblotting. These antibodies were demonstrated to recognize three neutralizing epitopes on peptides and the recombinant gp41 in ELISA-assay and immunoblotting. These results indicated that both candidate multi-epitope-vaccines could induce high levels of antibodies of predefined epitope-specificity which recognized a few of neutralizing epitopes on peptides and protein, providing experimental evidence for the new strategy to develop an effective neutralizing-antibody-based multi-epitope-vaccine against HIV-1.

Wallace M, Pyzalski R, Horejsh D, Brown C, Djavani M, Lu Y, Hanson JM, Mitchen JL, Perlman SB, Pauza CD. · Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53705-1532, USA. · Virology. · Pubmed #10964769 No free full text.

Abstract: Mechanisms of acute retroviral pathogenesis have been examined during primary infection of rhesus macaques with simian-human immunodeficiency virus 89.6PD (SHIV(89.6PD)). During acute infection, between initial exposure and establishment of antigen-specific immune responses that stabilize the virus burden, rapid immune system changes influence the viral set-point and dictate subsequent steps in disease progression. In a previous study, we described specific patterns of lymphocyte activation during acute SHIV(89.6PD) infection. We now extend these studies to describe lymphoid tissue activation, using whole body positron emission tomography (PET) and the radioactive tracer 2-[(18)F]fluorodeoxyglucose (FDG). Within a few days after primary infection by intravenous, intrarectal, or intravaginal routes, PET-FDG imaging revealed a distinct pattern of lymphoid tissue activation centered on axillary, cervical, and mediastinum lymph nodes. Increased tissue FDG uptake preceded fulminant virus replication at these sites, suggesting that a diffusible factor of host or viral origin was responsible for lymphoid tissue changes. These data show that activation of lymphoid tissues in the upper body is an early response to virus infection and that diffusible mediators of activation might be important targets for vaccine or therapeutic intervention strategies.

Baba TW, Liska V, Hofmann-Lehmann R, Vlasak J, Xu W, Ayehunie S, Cavacini LA, Posner MR, Katinger H, Stiegler G, Bernacky BJ, Rizvi TA, Schmidt R, Hill LR, Keeling ME, Lu Y, Wright JE, Chou TC, Ruprecht RM. · Department of Cancer Immonology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. · Nat Med. · Pubmed #10655110 No free full text.

Abstract: Although maternal human immunodeficiency virus type 1 (HIV-1) transmission occurs during gestation, intrapartum and postpartum (by breast-feeding), 50-70% of all infected children seem to acquire HIV-1 shortly before or during delivery. Epidemiological evidence indicates that mucosal exposure is an important aspect of intrapartum HIV transmission. A simian immunodeficiency virus (SIV) macaque model has been developed that mimics the mucosal exposure that can occur during intrapartum HIV-1 transmission. To develop immunoprophylaxis against intrapartum HIV-1 transmission, we used SHIV-vpu+ (refs. 5,6), a chimeric simian-human virus that encodes the env gene of HIV-IIIB. Several combinations of human monoclonal antibodies against HIV-1 have been identified that neutralize SHIV-vpu+ completely in vitro through synergistic interaction. Here, we treated four pregnant macaques with a triple combination of the human IgG1 monoclonal antibodies F105, 2G12 and 2F5. All four macaques were protected against intravenous SHIV-vpu+ challenge after delivery. The infants received monoclonal antibodies after birth and were challenged orally with SHIV-vpu+ shortly thereafter. We found no evidence of infection in any infant during 6 months of follow-up. This demonstrates that IgG1 monoclonal antibodies protect against mucosal lentivirus challenge in neonates. We conclude that epitopes recognized by the three monoclonal antibodies are important determinants for achieving substantial protection, thus providing a rational basis for AIDS vaccine development.

Lu Y, Nerurkar VR, Dashwood WM, Woodward CL, Ablan S, Shikuma CM, Grandinetti A, Chang H, Nguyen HT, Wu Z, Yamamura Y, Boto WO, Merriwether A, Kurata T, Detels R, Yanagihara R. · Retrovirology Research Laboratory, Hawaii AIDS Research Consortium, and Native Hawaiian Health Research Program, Pacific Biomedical Research Center, University of Hawaii at Manoa, Honolulu, Hawaii 96816, USA. · Int J Infect Dis. · Pubmed #10575146 No free full text.

Abstract: BACKGROUND: A 32-base pair (bp) deletion mutation in the beta-chemokine receptor CCR5 gene has been associated with resistance against human immunodeficiency virus type 1 (HIV-1) infection and disease. Large-scale studies conducted among Caucasians indicate that individuals who are homozygous for this deletion mutation (D32/D32) are protected against HIV-1 infection despite multiple high-risk exposures, whereas CCR5/ D32 heterozygotes have a slower progression to acquired immunodeficiency syndrome (AIDS). OBJECTIVE: To determine the genotype and allele frequencies of the CCR5 gene 32-bp deletion mutation among ethnically diverse non-Caucasian populations. METHODS: DNA, extracted from blood collected between 1980 and 1997 from 1912 individuals belonging to various ethnic groups, including 363 Caucasians, 303 Puerto Rican Hispanics, 150 Africans, 606 Asians, and 490 Pacific Islanders, were analyzed for the CCR5 gene 32-bp deletion mutation by a polymerase chain reaction (PCR)-based assay, using an oligonucleotide primer pair designed to discriminate CCR5 alleles without restriction endonuclease analysis. RESULTS: The comparative frequency of CCR5/D32 heterozygosity was 61 of 363 (16. 8%) in Caucasians, 17 of 303 (5.6%) in Puerto Rican Hispanics, 9 of 490 (1.8%) in Pacific Islanders, 0 of 606 (0%) in Asians, and 0 of 150 (0%) in Africans. CONCLUSIONS: The data confirm the high frequency of CCR5/D32 heterozygosity among Caucasians. Intermediate and low-level D32 allele frequencies among Puerto Rican Hispanics and Hawaiians could be attributed to recent European Caucasian gene flow. By contrast, the inability to detect the D32 allele among Asians and other Pacific Islander groups suggests that other mechanisms are responsible for resistance to HIV-1 infection in these populations.

Shinohara K, Sakai K, Ando S, Ami Y, Yoshino N, Takahashi E, Someya K, Suzaki Y, Nakasone T, Sasaki Y, Kaizu M, Lu Y, Honda M. · Division of Biosafety Control and Research, National Institute of Infectious Diseases, Tokyo, Japan. · J Gen Virol. · Pubmed #10355770 links to  free full text

Abstract: A highly pathogenic simian/human immunodeficiency virus (SHIV), designated C2/1, was obtained by serum passages in cynomolgus monkeys of p-SHIV, an SHIV strain that contains the env gene of pathogenic human immunodeficiency virus type 1 89.6. CD4+ lymphocyte depletion was induced within 1 week of the SHIV-C2/1 infection in peripheral blood as well as in various lymphoid organs in all the animals tested, with symptoms of diarrhoea and no increase in body weight, followed by intense viraemia. Serum antibody against Env protein was detected from 4 weeks after the virus infection, while the anti-Gag antibody response was absent in the SHIV-C2/1-infected animals. In contrast, both anti-Gag and anti-Env antibody responses were present in animals infected with p-SHIV or the non-pathogenic SHIV-MN. Sequencing of the env gene of isolates of SHIV-C strains showed conserved amino acid changes in the Env C2 and V3 regions that included changes to negatively charged amino acids, in the cytoplasmic region of gp41 that included a 42 amino acid deletion, and in the Nef protein. The pathogenic SHIV-C2/1-monkey model suggests that virus-specific pathogenicity in SHIV infection may be associated with the absence of anti-Gag antibody responses in animals and may be caused by genetic changes during serum passage in vivo.

Lewis MG, Yalley-Ogunro J, Greenhouse JJ, Brennan TP, Jiang JB, VanCott TC, Lu Y, Eddy GA, Birx DL. · Henry M. Jackson Foundation, Walter Reed Army Institute of Research, Rockville, Maryland 20850, USA. · J Virol. · Pubmed #9882330 links to  free full text

Abstract: Two live attenuated single-deletion mutant simian immunodeficiency virus (SIV) constructs, SIV239Deltanef and SIVPBj6.6Deltanef, were tested for their abilities to stimulate protective immunity in macaques. During the immunization period the animals were examined for specific immune responses and virus growth. Each construct generated high levels of specific immunity in all of the immunized animals. The SIV239Deltanef construct was found to grow to high levels in all immunized animals, with some animals remaining positive for virus isolation and plasma RNA throughout the immunization period. The SIVPBj6.6Deltanef was effectively controlled by all of the immunized animals, with virus mostly isolated only during the first few months following immunization and plasma RNA never detected. Following an extended period of immunization of over 80 weeks, the animals were challenged with a pathogenic simian-human immunodeficiency virus (SHIV) isolate, SIV89. 6PD, by intravenous injection. All of the SIV239Deltanef-immunized animals became infected with the SHIV isolate; two of five animals eventually controlled the challenge and three of five animals, which failed to check the immunizing virus, progressed to disease state before the unvaccinated controls. One of five animals immunized with SIVPBj6.6Deltanef totally resisted infection by the challenge virus, while three others limited its growth and the remaining animal became persistently infected and eventually died of a pulmonary thrombus. These data indicate that vaccination with attenuated SIV can protect macaques from disease and in some cases from infection by a divergent SHIV. However, if animals are unable to control the immunizing virus, potential damage that can accelerate the disease course of a pathogenic challenge virus may occur.