Acquired Immunodeficiency Syndrome: Chun TW

Berrey MM, Schacker T, Collier AC, Shea T, Brodie SJ, Mayers D, Coombs R, Krieger J, Chun TW, Fauci A, Self SG, Corey L. · Department of Medicine, University of Washington, Seattle, WA, USA. · J Infect Dis. · Pubmed #11319682 No free full text.

Abstract: Immunologic data supporting immediate antiretroviral therapy in primary human immunodeficiency virus type 1 (HIV-1) infection are emerging; however, clinical benefit has not been demonstrated. The clinical and virologic course of 47 patients who were enrolled from September 1993 through June 1996 and who were not initially treated with potent therapy was compared with the course of 20 patients who immediately began therapy with zidovudine, lamivudine, and indinavir. Demographic and baseline laboratory data were comparable. During 78 weeks of follow-up, the early-treatment cohort showed a reduced frequency of opportunistic infections (5% vs. 21.3%; relative risk, 0.11; P=.02), less frequent progression to AIDS (13% vs. 0%), and significantly less frequent nonopportunistic mucocutaneous disorders and respiratory infections (P<.01). Plasma HIV-1 RNA levels were <50 copies/mL in all patients who continued therapy; however, after 9--12 months, HIV-1 remained detectable in latently infected CD4(+) T cells and in lymph node mononuclear cells. Combination antiretroviral therapy during primary HIV-1 infection demonstrated a decreased frequency of minor opportunistic infections, mucocutaneous disorders, and respiratory infections and reduced progression to AIDS.

Nishimura Y, Sadjadpour R, Mattapallil JJ, Igarashi T, Lee W, Buckler-White A, Roederer M, Chun TW, Martin MA. · Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. · Proc Natl Acad Sci U S A. · Pubmed #19416840 No free full text.

Abstract: We and others have reported that the vast majority of virus-producing CD4(+) T cells during the acute infection of rhesus macaques with simian immunodeficiency virus (SIV) or CXCR4 (X4)-using simian/human immunodeficiency viruses (SHIVs) exhibited a nonactivated phenotype. These findings have been extended to show that resting CD4(+) T lymphocytes collected from SIV- or X4-SHIV-infected animals during the first 10 days of infection continue to release virus ex vivo. Furthermore, we observed high frequencies of integrated viral DNA (up to 5.1 x 10(4) DNA copies per 10(5) cells) in circulating resting CD4(+) T cells during the first 10 days of the infection. Integration of SIV DNA was detected only in memory CD4(+) T cells and SHIVs preferentially integrated into resting naïve CD4(+) T cells. Taken together, these results show that during the acute infection large numbers of resting CD4(+) T cells carry integrated nonhuman primate lentiviral DNA and are the major source of progeny virions irrespective of coreceptor usage. Prompt and sustained interventions are therefore required to block the rapid systemic dissemination of virus and prevent an otherwise fatal clinical outcome.

Chun TW, Justement JS, Sanford C, Hallahan CW, Planta MA, Loutfy M, Kottilil S, Moir S, Kovacs C, Fauci AS. · Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. · Proc Natl Acad Sci U S A. · Pubmed #14983032 links to  free full text

Abstract: CD8+ T cells are critical for effective host defenses against viral infections. Studies addressing HIV-induced immune responses in infected individuals have suggested that CD8+ T cells play an important role in controlling viral replication. However, despite an abundance of HIV-specific CD8+ T cells, HIV is not contained in many untreated patients. Active HIV replication is associated with numerous immunologic changes, the most notable and consistent of which is an increase in CD8+ T cells expressing CD38. Previous studies have demonstrated that the expression of CD38 on CD8+ T cells is associated with poor prognostic outcome in infected individuals with detectable plasma viremia; however, the relationship between the expression of CD38 and the frequency of HIV-specific CD8+ T cells is unclear. We demonstrate a correlation between levels of HIV-specific CD8+ T cells and levels of CD8+ T cells expressing CD38 in untreated patients. The distribution of HIV-specific CD8+ T cells was heavily skewed toward CD38+CD8+ T cells in patients with a high percentage of CD38+CD8+ T cells. Spontaneous/Fas-mediated apoptosis in CD38+CD8+ T cells was significantly higher in patients with high percentages of CD38+CD8+ T cells. Our data suggest that a substantial proportion of the HIV-specific CD8+ T cells present in CD38+CD8+ T cells in patients with active viral replication arise by HIV-driven aberrant immune activation and may not manifest effective cytolytic activity against infected targets due to a high degree of susceptibility to apoptosis, thus providing an explanation of why HIV is not successfully contained by CD8+ T cells in such individuals.

Hamer DH, Bocklandt S, McHugh L, Chun TW, Blumberg PM, Sigano DM, Marquez VE. · Laboratory of Biochemistry, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. · J Virol. · Pubmed #12970407 links to  free full text

Abstract: Drugs that induce human immunodeficiency virus type 1 (HIV-1) replication could be used in combination with highly active antiretroviral therapy (HAART) to reduce the size of the latent reservoir that is in part responsible for viral persistence. Protein kinase C (PKC) is a logical target for such drugs because it activates HIV-1 transcription through multiple mechanisms. Here we show that HIV-1 gene expression can be induced by potent synthetic analogues of the lipid second messenger diacylglycerol (DAG) synthesized on a five-member ring platform that reduces the entropy of binding relative to that of the more flexible DAG template. By varying the alkyl side chains of these synthetic DAG lactones, it was possible to maximize their potency and ability to render latently infected T cells sensitive to killing by an anti-HIV-1 immunotoxin while minimizing the side effects of CD4 and CXCR4 downregulation and tumor necrosis factor alpha upregulation. The two lead compounds, LMC03 and LMC07, regulated a series of PKC-sensitive genes involved in T-cell activation and induced viral gene expression in peripheral blood mononuclear cells from HIV-1-infected individuals. These studies demonstrate the potential for the rational design of agents that, in conjunction with HAART and HIV-specific toxins, can be used to decrease or eliminate the pool of latently infected reservoirs by forcing viral expression.

Chen X, Scala G, Quinto I, Liu W, Chun TW, Justement JS, Cohen OJ, vanCott TC, Iwanicki M, Lewis MG, Greenhouse J, Barry T, Venzon D, Fauci AS. · Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland, USA. · Nat Med. · Pubmed #11689887 No free full text.

Abstract: The antigenic polymorphism of HIV-1 is a major obstacle in developing an effective vaccine. Accordingly, we screened random peptide libraries (RPLs) displayed on phage with antibodies from HIV-infected individuals and identified an array of HIV-specific epitopes that behave as antigenic mimics of conformational epitopes of gp120 and gp41 proteins. We report that the selected epitopes are shared by a collection of HIV-1 isolates of clades A-F. The phage-borne epitopes are immunogenic in rhesus macaques, where they elicit envelope-specific antibody responses. Upon intravenous challenge with 60 MID50 of pathogenic SHIV-89.6PD, all monkeys became infected; however, in contrast to the naive and mock-immunized monkeys, four of five mimotope-immunized monkeys experienced lower levels of peak viremia, followed by viral set points of undetectable or transient levels of viremia and a mild decline of CD4+ T cells, and were protected from progression to AIDS-like illness. These results provide a new approach to the design of broadly protective HIV-1 vaccines.

Moir S, Malaspina A, Li Y, Chun TW, Lowe T, Adelsberger J, Baseler M, Ehler LA, Liu S, Davey RT, Mican JA, Fauci AS. · Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. · J Exp Med. · Pubmed #10974030 links to  free full text

Abstract: The impact of HIV-associated immunopathogenesis on B cells has been largely associated with indirect consequences of viral replication. This study demonstrates that HIV interacts directly with B cells in both lymphoid tissues and peripheral blood. B cells isolated from lymph node and peripheral blood mononuclear cells (PBMCs) of 4 and 23 chronically infected patients, respectively, demonstrated similar capacities to pass virus to activated HIV-negative PBMCs when compared with CD4(+) cells from the same patients. However, in contrast to T cells, virus associated with B cells was surface bound, as shown by its sensitivity to pronase and the staining pattern revealed by in situ amplification of HIV-1 RNA. Cell sorting and ligand displacing approaches established that CD21 was the HIV-binding receptor on B cells, and that this association was mediated through complement-opsonized virus. These B cells were also found to express significantly lower levels of CD21 compared with HIV-negative individuals, suggesting a direct perturbing effect of HIV on B cells. These findings suggest that B cells, although they themselves are not readily infected by HIV, are similar to follicular dendritic cells in their capacity to serve as extracellular reservoirs for HIV-1. Furthermore, B cells possess the added capability of circulating in peripheral blood and migrating through tissues where they can potentially interact with and pass virus to T cells.