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Query: UMLS:C0001175 (AIDS)
 120,706 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the impact of the diversity of antigen recognition by T lymphocytes on disease pathogenesis, we must be able to identify and analyze simultaneously cytotoxic T-lymphocyte (CTL) responses specific for multiple viral epitopes. Many of the studies of the role of CD8(+) CTLs in AIDS pathogenesis have been done with simian immunodeficiency virus (SIV)- and simian-human immunodeficiency virus (SHIV)-infected rhesus monkeys. These studies have frequently made use of the well-defined SIV Gag CTL epitope p11C,C-M presented to CTL by the HLA-A homologue molecule Mamu-A*01. In the present study we identified and fine mapped two novel Mamu-A*01-restricted CTL epitopes: the SIVmac Pol-derived epitope p68A (STPPLVRLV) and the human immunodeficiency virus type 1 (HIV-1) Env-derived p41A epitope (YAPPISGQI). The frequency of CD8(+) CTLs specific for the p11C,C-M, p68A, and p41A epitopes was quantitated in the same animals with a panel of tetrameric Mamu-A*01/peptide/beta2m complexes. All SHIV-infected Mamu-A*01(+) rhesus monkeys tested had a high frequency of SIVmac Gag-specific CTLs to the p11C,C-M epitope. In contrast, only a fraction of the monkeys tested had detectable CTLs specific for the SIVmac Pol p68A and HIV-1 Env p41A epitopes, and these responses were detected at very low frequencies. Thus, the p11C,C-M-specific CD8(+) CTL response is dominant and the p41A- and p68A-specific CD8(+) CTL responses are nondominant. These results indicate that CD8(+) CTL responses to dominant CTL epitopes can be readily quantitated with the tetramer technology; however, CD8(+) CTL responses to nondominant epitopes, due to the low frequency of these epitope-specific cells, may be difficult to detect and quantitate by this approach.
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PMID:Use of major histocompatibility complex class I/peptide/beta2M tetramers to quantitate CD8(+) cytotoxic T lymphocytes specific for dominant and nondominant viral epitopes in simian-human immunodeficiency virus-infected rhesus monkeys. 1036 94

The gag p17 matrix sequences of human immunodeficiency virus type 1 (HIV-1) from seven infected mother-infant pairs were analyzed after perinatal transmission. The p17 matrix open reading frame was maintained in 143 of the 166 clones analyzed (86.2% frequency of intact p17 open reading frames). The functional domains essential for p17 matrix function in HIV-1 replication, including targeting of Gag to the plasma membrane, virus assembly and release, envelope glycoprotein incorporation into virus particle, virus entry, and localization of the virus preintegration complex to the nucleus of nondividing cells, were highly conserved in most of the sequences. In addition, examination of the three-dimensional structure of the p17 matrix protein in mother-infant isolates showed a high degree of conservation of amino acids required for correct folding and biological activity. Several amino acid motifs common to most of the mother-infant pairs sequences, including pair-specific signature sequences, were observed. There was a low degree of heterogeneity of gag p17 sequences within mothers, within infants, and between mother-infant pairs, but the distances were greater between epidemiologically unlinked individuals. Phylogenetic analyses of 166 mother-infant pairs and 181 other p17 sequences available from HIV-1 databases revealed distinct clusters for each mother-infant pair and for other p17 sequences. In conclusion, these findings indicate that an intact and functional gag p17 matrix is maintained during maternal-fetal transmission and that several motifs in p17 may be associated with perinatal transmission.
AIDS Res Hum Retroviruses 1999 Jul 01
PMID:Characterization of mother-infant HIV type 1 gag p17 sequences associated with perinatal transmission. 1040 24

Previously, we described the derivation of a pathogenic strain of simian-human immunodeficiency virus (SHIV(KU-2)) consisting of the tat, rev, vpu, and env genes of HIV-1 (strain HXB2) in a genetic background of SIV(mac)239 that causes AIDS and productive infection of the CNS in rhesus macaques (Macca mulatta) (Raghavan et al., 1997, Brain Pathol. 7, 851-861). We report here on the characterization of a molecular clone of SHIV(KU-2), designated SHIV(KU-2MC4), that caused CD4(+) T cell loss as well as neurological and renal disease in macaques. DNA sequence analysis of selected SIV regions of SHIV(KU-2MC4) revealed 10 nucleotide changes in the LTR, whereas Gag, Vif, Vpr, Vpx, and Nef had 1, 1, 1, 2, and 13 predicted amino acid substitutions, respectively, compared to SIV(mac)239. DNA sequence analysis of HIV-1 derived regions of SHIV(KU-2MC4) revealed 2, 1, 2, and 18 predicted amino acid substitutions in the Tat, Rev, Vpu, and Env proteins, respectively, when compared to SHIV-4. Unlike the parental SHIV-4, which is not tropic for macrophages, SHIV(KU-2MC4) replicated efficiently in macrophage cultures as determined by p27 assays. However, despite the numerous changes in the Env protein and newly acquired tropism for macrophages, SHIV(KU-2MC4), like the parental SHIV-4, used CXCR4 exclusively as its coreceptor for entry into susceptible cells. Inoculation of SHIV(KU-2MC4) into two rhesus macaques resulted in severe infection in which the numbers of circulating CD4(+) T cells in the blood declined rapidly by 2 weeks postinoculation and virus producing cells in the peripheral blood mononuclear cells were identified throughout the course of infection. At the time of euthanasia (20 and 22 weeks), both macaques had lost a significant amount of weight and had no circulating CD4(+) T cells. In addition, one macaque developed intension tremors and uncoordinated movements. Virological examination of tissues at necropsy revealed active virus replication in both lymphoid and nonlymphoid tissues such as the lung and brain. Histological examination revealed that the induced immunodeficiency was associated with lymphoid depletion of the lymph nodes and spleen, opportunistic infections, lentiviral encephalitis, and severe glomerulosclerosis of the kidney. This molecular clone will serve as the basis for analyzing the molecular determinants through which SHIV(KU-2) causes severe CD4(+) T cell loss, neurological disease, and SHIV nephropathy in rhesus macaques.
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PMID:Derivation and biological characterization of a molecular clone of SHIV(KU-2) that causes AIDS, neurological disease, and renal disease in rhesus macaques. 1041 64

An important aspect of vaccine development involves delivery of antigens to antigen-presenting cells for the induction of potent antigen-specific T lymphocyte responses. We investigated the effect of a cationic liposome, lipofectin, on delivery of whole proteins to human dendritic cells (DCs) derived from blood mononuclear cells by culture in interleukin 4 and granulocyte-monocyte colony-stimulating factor for stimulation of human immunodeficiency virus type 1 (HIV-1)-specific memory cytotoxic T lymphocyte (CTL) responses. Delivery of HIV-1 Gag, Pol, and Env proteins to DCs by lipofectin stimulated greater anti-HIV-1 memory CTL responses in cells from HIV-1-infected subjects than those induced by DCs loaded with protein alone. The CTLs were CD8+ and HLA class I restricted. Antigen presentation was enhanced by chloroquine, but blocked by brefeldin A and peptide aldehyde inhibitors of proteasomes, indicating that the classic MHC class I cytosolic pathway was used for processing and presentation of HIV-1 protein by the DCs. Stimulation of anti-HIV-1 CTLs by this safe, inexpensive, and broadly applicable approach may be used in DC-based therapies for HIV-1 infection.
AIDS Res Hum Retroviruses 1999 Jul 20
PMID:Delivery of liposome-encapsulated HIV type 1 proteins to human dendritic cells for stimulation of HIV type 1-specific memory cytotoxic T lymphocyte responses. 1044 13

Development of an effective vaccine against HIV-1 will likely require the induction of a broad array of immune responses, including virus-specific CTLs and neutralizing antibodies. One promising vaccine approach involves live recombinant canarypox (CP)-based vectors (ALVAC) containing multiple HIV-1 genes. In phase I clinical trials in HIV-1-seronegative volunteers, the cumulative rate of detection of HIV-1-specific CTLs has been as high as 60-70%. In the present study, the factors associated with CTL responsiveness were evaluated in a subset of vaccinees immunized with a CP vector expressing portions of the gag, pro, and env genes of HIV-1 (ALVAC-HIV). CTL responses were detected in one of seven examined. While the responding individual had both CD4+ and CD8+ CTLs directed at multiple HIV-1 antigens, this response was not detectable 1 year after the last vaccination. In-depth characterization of "CTL nonresponders" showed that nonresponsiveness was not associated with defects in antigen processing or presentation. A generalized defect in CTL responsiveness was ruled out by parallel assays to detect CMV-specific CTLs from these same volunteers. Furthermore, HIV-1-specific memory CTLs were not detectable by peptide stimulation or by a novel technique for flow cytometric visualization of Gag epitope-specific T lymphocytes while HIV-1-seropositive donors frequently had 0.1-3% of CD8+ cells stain positively for this epitope (SLYNTVATL). Taken together, these results suggest that the lack of detectable HIV-1 CTLs in these volunteers was not due to classic MHC-linked nonresponsiveness.
AIDS Res Hum Retroviruses 1999 Jul 20
PMID:An algorithm for evaluating human cytotoxic T lymphocyte responses to candidate AIDS vaccines. 1044 14

CTL lines directed against HIV-1 antigens were generated from infected individuals and were transduced by the HMB-K(b)HuIFNbeta vector, resulting in low, constitutive expression of interferon beta (IFN-beta). The IFN-beta-transduced cells showed markedly increased HIV-1-specific, MHC class I-restricted CTL activity against HIV-1-LAI Gag, Pol, or Env antigens. This effect of IFN-beta was correlated with an overexpression of RANTES and completely abrogated by RANTES-blocking antibody. The present results provide the first evidence that IFN-beta transduction of CTL lines enhances HIV-specific cytotoxic activities through an upregulation of RANTES production. The efficient elimination of HIV-infected cells by IFN-beta-transduced CTL lines makes this gene therapy approach an attractive treatment for AIDS.
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PMID:Acquired constitutive expression of interferon beta after gene transduction enhances human immunodeficiency virus type 1-specific cytotoxic T lymphocyte activity by a RANTES-dependent mechanism. 1044 20

There are several major strategies against HIV/AIDS. Of these, the gene therapy is a novel, challenging, and promising one. The target genes, which have been extensively studied for the potential gene therapy of HIV/AIDS, include those of cellular and viral origins. Especially, trans-dominant negative Tat, Rev, Env, Pol, and Gag mutants of HIV have currently attracted considerable attention. In this brief review, we summarize the nature of the HIV/SIV mutants of this category and discuss their future use for gene therapy with special reference to the dominant negative Gag mutants of HIV-1.
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PMID:Inhibition of HIV/SIV replication by dominant negative Gag mutants. 1045 87

HIV-1-specific cytotoxic T cell (CTL) activity has been suggested to correlate with protection from progression to AIDS. We have examined the relationship between HIV-specific CTL activity and maintenance of peripheral blood CD4+ T lymphocyte counts and control of viral load in 17 long-term survivors (LTSs) of HIV-1 infection. Longitudinal analysis indicated that the LTS cohort demonstrated a decreased rate of CD4+ T cell loss (18 cells/mm3/year) compared with typical normal progressors (approximately 60 cells/mm3/year). The majority of the LTSs had detectable, variable, and in some individuals, quite high (>10(4) RNA copies/ml) plasma viral load during the study period. In a cross-sectional analysis, HIV-specific CTL activity to HIV Gag, Pol, and Env proteins was detectable in all 17 LTSs. Simultaneous analysis of HIV-1 Gag-Pol, and Env-specific CTLs and virus load in protease inhibitor-naive individuals showed a significant inverse correlation between Pol-specific CTL activity and plasma HIV-1 RNA levels (p = 0.001). Furthermore, using a mixed linear effects model the combined effects of HIV-1 Pol- and Env-specific CTL activity on the viral load were significantly stronger than the effects of HIV-1 Pol-specific CTL activity alone on predicted virus load. These data suggest that the presence of HIV-1-specific CTL activity in HIV-1-infected long-term survivors is an important component in the effective control of HIV-1 replication.
AIDS Res Hum Retroviruses 1999 Sep 01
PMID:Human immunodeficiency virus type 1-specific cytotoxic T lymphocyte activity is inversely correlated with HIV type 1 viral load in HIV type 1-infected long-term survivors. 1048 Jun 35

In an attempt to develop an immunization strategy to induce mucosal and circulatory antibodies against SIV antigens, we have investigated the potential of attenuated recombinant vaccinia virus to deliver SIV antigens (gp160 of SIVmac239) to mucosal surfaces of mice. After systemic or mucosal (intragastric, intranasal, or intrarectal) immunization with vaccinia virus-SIV Env recombinants the immune responses against the envelope glycoprotein of SIV, as well as against vaccinia virus antigens, were assessed by ELISA of serum, saliva, and intestinal and vaginal secretions. All immunization routes induced specific antibody titers against gp160 in both serum and external secretions. Recall responses against SIV were found to be acquired after administration of SIVmac239 Env and Gag antigens in a virus-like particle (VLP) form by the same mucosal routes as those used for the priming with recombinant vaccinia virus. The results obtained demonstrate the potential of vaccinia virus recombinants to elicit a primary immune response at mucosal surfaces, which could be enhanced by delivering the same antigen in the form of VLPs.
AIDS Res Hum Retroviruses 1999 Nov 01
PMID:Induction of immune responses to SIV antigens by mucosally administered vaccines. 1055 10

The human immunodeficiency virus type 1 (HIV-1) genome encodes a highly conserved 16 kDa regulatory gene product, Vpr (viral protein of regulation, 96 amino acid residues), which is incorporated into virions, in quantities equivalent to those of the viral Gag proteins. In the infected cells, Vpr is believed to function in the early phase of HIV-1 replication, including nuclear migration of preintegration complex, transcription of the provirus genome and viral multiplication by blocking cells in the G2 phase. Vpr has a critical role in long-term AIDS disease by inducing infection in nondividing cells such as monocytes and macrophages. Mutations have suggested that the N-terminal domain of Vpr encompassing the first 40 residues could be required for nuclear localization, packaging into virions and binding of transcription factor (TFIIB, Sp1), viral proteins (p6) and cellular proteins (RIP1, UNG, karyopherins). To gain insight into the structure-function relationship of Vpr, (1-51)Vpr was synthesized and its structure analyzed by circular dichroism and two-dimensional 1H NMR in aqueous trifluoroethanol (30%) solution and refined by restrained molecular dynamics. The structure is characterized by three turns around the first three prolines, Pro5, Pro10, Pro14, followed by a long amphipathic alpha helix-turn-alpha helix (Asp17-Ile46) motif ended by a turn extending from Tyr47 to Thr49. The alpha helix-turn-alpha helix motif and the amphipathic helix are well known for being implicated in protein-protein or protein-nucleic acid interaction. Therefore structural characteristics of the (1-51) N-terminal fragment of Vpr could explain why this region of Vpr plays a role in several biological functions of this protein.
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PMID:NMR structure of the (1-51) N-terminal domain of the HIV-1 regulatory protein Vpr. 1056 76


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