Acquired Immunodeficiency Syndrome: Planet Earth

Mavoungou E, Touré FS, Yaba P, Sall A, Délicat A, Poaty-Mavoungou V. · Centre International de Recherches Médicales de Franceville, Gabon. · J Med Primatol. · Pubmed #10733203 No free full text.

Abstract: We have previously demonstrated that peptide immunization restimulates the memory CD4 T-cell response, but fails to induce cytotoxic T lymphocyte (CTL) in cynomolgus macaques. To examine the nature of protective immunity to simian immunodeficiency virus (SIV) in this study, freshly isolated peripheral blood mononuclear cells (PBMC) from four infected juvenile cynomolgus macaques and from three uninfected control macaques were assessed for CTL activity monthly for 9 consecutive months, beginning 1 month after detection of infection. Target cells consisted of major histocompatibility (MHC) haploidentical parental PBMC which were stimulated with mitogen and then pulsed with heat-killed SIVcyn. CTL activity was demonstrated in PBMCs from all four infected animals. The effector cells are T cells which mediate cytotoxicity against SIVcyn-pulsed target cells in an MHC-restricted manner. Furthermore, the cytotoxicity is virus specific and predominantly, if not exclusively, mediated by CD8+ T cells; it is also MHC class I restricted. Incubation of target cells with pepstatin A during antigen pulsing prior to the cytotoxic assay inhibited target cell generation, suggesting that viral antigens are processed via an endocytic pathway.

Brodie SJ. · University of Washington School of Medicine, Virology Division, Seattle 98195, USA. · J Leukoc Biol. · Pubmed #10985251 links to  free full text

Abstract: Autopsy tissues from 2 cohorts of age-matched HIV-infected children with similar plasma viral load (>10(5) HIV RNA copies/ml), but with distinct AIDS-associated disease manifestations, were examined for sites of persistent HIV replication. One group consisted of 3 children with severe lymphoid atrophy and peripheral blood CD4+ T cell counts of < 10/mm . Another group was composed of 6 children with extensive hyperplasia of mucosal-associated lymphoid tissues and blood CD4+ T cell counts >500/mm3. Hyperplastic bronchiole- and gut-associated lymphoid tissues were characterized by extensive networks of germinal center follicular dendritic cells (FDC) containing large amounts of immune-complexed virion RNA. Conversely, pulmonary and gastrointestinal tissues from children with severe CD4+ T cell depletion were devoid of any secondary lymphoid structures, yet these tissues also harbored high concentrations of HIV RNA. Dual in situ procedures showed that only macrophage (Mphi) within these sites contained tat fusion transcripts, a product of post-transcriptional splicing and a correlate of productive infection. When examining explant cultures of Mphi and FDC, only Mphi harbored HIV tat mRNA and only Mphi demonstrated budding retroviral particles. Hence, germinal center FDC in secondary lymphoid tissues are key reservoirs of immune-complexed HIV RNA and are likely to contribute to AIDS-associated lymphoproliferations; however, these cells do not support HIV replication, and failure to do so results from a post-transcriptional block in the virus life cycle. Moreover, gut and pulmonary Mphi represent a lineage of cells that are permissive to HIV replication and contribute significantly to the high viral load in children with severe CD4+ T cell depletion. It will be important to identify the molecular mechanisms that allow for these highly productive infections of Mphi.

Poaty-Mavoungou V, Onanga R, Yaba P, Delicat A, Dubreuil G, Mavoungou E. · Centre International de Recherches Médicales de Franceville, Gabon. · J Med Primatol. · Pubmed #11396861 No free full text.

Abstract: Six different species of nonhuman primates housed at the CIRMF Primate Center, cynomolgus monkeys (Macaca fascicularis), rhesus monkeys (Macaca mulatta), mandrills (Mandrillus sphinx), vervets (Cercopithecus aethiops pygerythrus), chimpanzees (Pan troglodyte) and baboons (Papio hamadryas), were evaluated for their natural killer cell activity and for the ability of their peripheral blood mononuclear cells to proliferate in response to known mitogens (concanavalin A, phytohemagglutinin and staphylococcal enterotoxin A) and to react with a panel of mouse monoclonal antibodies directed against human leukocyte surface antigens. Basic information on normal immune functions in these primates is important because of their use as experimental animal models for the study of human diseases such as acquired immunodeficiency syndrome (AIDS), hepatitis, loiasis and malaria.

Poaty-Mavoungou V, Touré FS, Tevi-Benissan C, Mavoungou E. · Centre International de Recherches Médicales de Franceville, Gabon. · Viral Immunol. · Pubmed #11952142 No free full text.

Abstract: We studied the innate immune system of Cynomolgus monkeys (Macaca fascicularis) experimentally infected via the vaginal mucosae with a virulent simian immunodeficiency virus isolate SIVmac251. Animals were evaluated for their natural killer (NK) cell activity, and for their antibody-dependent cellular cytotoxicity. NK cells from SIVmac251-infected macaques show impaired NK cell activity compared to cells from uninfected animals. Subsequent treatment of NK cells with interferon-a (IFN-alpha) or interleukin-12 (IL-12) alone partially restored the NK activity. However, either treatment of NK cells with both IFN-alpha and IL-12 completely reversed the impairment of cytotoxicity induced by simian immunodeficiency virus (SIV) infection. Incubation of NK cells from infected but not from uninfected monkeys with IFN-alpha and IL-12 for 8 days increased the percentage of CD16+/CD56+ cells twofold to five-fold and enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. Thus IFN-alpha and IL-12 greatly enhance both the NK cell and ADCC activities of peripheral blood cells from SIVmac251-infected animals and increase the number of NK cells in longer term culture. The combined effect of IFN-alpha and IL-12 in enhancing NK cell activity may provide a novel therapeutic approach for the restoration of depressed NK cell activity observed in human immunodeficiency virus (HIV)-infected patients.

Izumi Y, Ami Y, Matsuo K, Someya K, Sata T, Yamamoto N, Honda M. · AIDS Research Center. Division of Experimental Animal Research. Department of Pathology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640. Japan. · J Virol. · Pubmed #14645581 links to  free full text

Abstract: To be effective, a vaccine against human immunodeficiency virus type 1 (HIV-1) must induce virus-specific T-cell responses and it must be safe for use in humans. To address these issues, we developed a recombinant vaccinia virus DIs vaccine (rDIsSIVGag), which is nonreplicative in mammalian cells and expresses the full-length gag gene of simian immunodeficiency virus (SIV). Intravenous inoculation of 10(6) PFU of rDIsSIVGag in cynomologus macaques induced significant levels of gamma interferon (IFN-gamma) spot-forming cells (SFC) specific for SIV Gag. Antigen-specific lymphocyte proliferative responses were also induced and were temporally associated with the peak of IFN-gamma SFC activity in each macaque. In contrast, macaques immunized with a vector control (rDIsLacZ) showed no significant induction of antigen-specific immune responses. After challenge with a highly pathogenic simian-human immunodeficiency virus (SHIV), CD4(+) T lymphocytes were maintained in the peripheral blood and lymphoid tissues of the immunized macaques. The viral set point in plasma was also reduced in these animals, which may be related to the enhancement of virus-specific intracellular IFN-gamma(+) CD8(+) cell numbers and increased antibody titers after SHIV challenge. These results demonstrate that recombinant DIs has potential for use as an HIV/AIDS vaccine.

Kiepiela P, Smith AN, Rosenberg E. · Nelson R Mandela School of Medicine, University of Kwazulu-Natal, HIV Pathogenesis Programme, DDMRI, 719 Umbilo Road, Congella, Durban, 4013 Natal, South Africa. · Best Pract Res Clin Obstet Gynaecol. · Pubmed #15778113 No free full text.

Abstract: Infection with HIV may develop to AIDS at different rates in different individuals, with a spectrum varying from rapid progression to long-term non-progression. The variable course of HIV-1 infection causes emotional trauma for the infected person and complicates the design and interpretation of therapeutic trials because of unrecognized differences in prognosis. Owing to the variable clinical expression of HIV infection, the use of non-clinical disease markers has become important to patient management. Thus, it is essential to have tests which can accurately assess the stage of infection in an individual, as well as predict its course and monitor its progression. These laboratory tests are valuable during the period of clinical latency and subsequently supplement various clinical parameters.