Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Production of the structural and enzymatic proteins of type 1 human immunodeficiency virus (HIV-1) is controlled by the rev regulatory gene product. The 116-amino acid Rev protein acts by binding to the Rev response element (RRE), a complex RNA stem-loop structure located within the env gene of HIV. Rev exerts a series of posttranscriptional effects, including the inhibition of viral RNA splicing, the activation of nuclear export of incompletely spliced viral RNAs, and the enhancement of translation of RRE-containing RNAs. Our studies now demonstrate that at least one member of the SR family of splicing factors, SF2/ASF, specifically binds to a subregion of the RRE in vitro in a Rev-dependent manner. Furthermore, expression of high levels of SF2/ASF inhibits Rev function and impairs HIV replication in vivo. Both the in vitro binding of SF2/ASF to the Rev/RRE complex and the in vivo inhibition of Rev action by SF2/ASF are abrogated by mutation of the N-terminal RNA recognition motif but are not affected by mutation of the C-terminal arginine-serine-rich domain. These findings suggest that Rev inhibition of HIV splicing likely involves recruitment of the essential splicing factor SF2/ASF to the Rev/RRE complex. However, these inhibitory effects of Rev on viral RNA splicing are apparently overcome by augmenting the intracellular levels of SF2/ASF expression.
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PMID:HIV Rev-dependent binding of SF2/ASF to the Rev response element: possible role in Rev-mediated inhibition of HIV RNA splicing. 902 67

Mitogen-activated T cell lines may be reproducibly used to identify relatively conserved HIV-1 epitopes that dominate CTL recognition of HIV-infected cells. Using a combination of nested truncations of HIV-vaccinia recombinants encoding HIV-1LAI Env and overlapping peptides that span the coding regions of the HIV-1 SF2 subclone of env, gag, nef, rev, and tat, we have mapped the immunodominant, relatively conserved CTL epitopes recognized by 25 HIV-seropositive individuals with CD4 counts between 100 and 500/mm3 and no history of AIDS opportunistic infection. We could characterize at least 1 peptide CTL epitope recognized by the T cell lines of 18 of 25 of the subjects; the T cell lines from 2 additional subjects recognized HIV-vaccinia presenting targets, but no dominant peptide epitope was identified. CTL epitopes were most frequently encoded by gag (recognized by 16 of 25 patient T cell lines), followed by nef and env (11 of 25 each), and the RT region of pol (9 of 25). Tat and Rev were rarely the sites of CTL epitopes. The identified epitopes occurred predominantly in relatively conserved regions of HIV-1. The mean number of HIV peptides identified at a single time for each cell line was 2.7 +/- 1.7. Although no single peptide dominated CTL recognition in more than four individuals, clusters of epitopes were found in the N-terminal region of gp160 and in two central regions of Nef. The dominant HIV-1 CTL epitopes in infected patients were not predictable on the basis of MHC expression and varied widely in an MHC-diverse population.
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PMID:Recognition of a small number of diverse epitopes dominates the cytotoxic T lymphocytes response to HIV type 1 in an infected individual. 907 79

Novel approaches for the generation of more effective vaccines for HIV-1 are of significant importance. In this report we analyze the immunogenicity and efficacy of an HIV-1 DNA vaccine encoding env, rev and gag/pol in a chimpanzee model system. The immunized animals developed specific cellular and humoral immune responses. Animals were challenged with a heterologous chimpanzee titered stock of HIV-1 SF2 virus and followed for 48 weeks after challenge. Polymerase chain reaction coupled with reverse transcription (RT-PCR) results indicated infection in the control animal, whereas those animals vaccinated with the DNA constructs were protected from the establishment of infection. These studies serve as an important benchmark for the use of DNA vaccine technology for the production of protective immune responses.
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PMID:Protection of chimpanzees from high-dose heterologous HIV-1 challenge by DNA vaccination. 914

A combination AIDS vaccine approach consisting of priming with adenovirus-HIV-1MN gp160 recombinants followed by boosting with HIV-1SF2 gp120 was evaluated in chimpanzees. Long-lasting protection, requiring only three immunizations, was achieved against a low-dose challenge with the SF2 strain of HIV-1 and a subsequent high-dose SF2 challenge administered 1 year later without an intervening boost. Notably, neutralizing antibody responses against both clinical and laboratory isolates developed in three chimpanzees and persisted until the time of high-dose challenge. The possibility that cytotoxic T-lymphocytes contribute to low-dose protection of a chimpanzee lacking neutralizing antibodies is suggested. Our results validate the live vector priming/subunit booster approach and should stimulate interest in assessing this combination vaccine approach in humans.
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PMID:Long-term protection of chimpanzees against high-dose HIV-1 challenge induced by immunization. 917 92

We sought to determine whether the neurotoxin quinolinic acid (QUIN) was produced by macrophages or lymphocytes infected with isolates of HIV-1 with varying degrees of macrophage tropism derived from patients with varying stages of AIDS dementia complex (ADC). Highly macrophage tropic isolates and minimally macrophage tropic isolates were used to inoculate macrophages and QUIN production was measured. Similarly, QUIN production from macrophages was monitored using a purified cell free highly macrophage tropic isolate and laboratory isolates SF33 and SF2. Each of these experiments was also performed with lymphocytes. We found that macrophages infected with macrophage tropic isolates of HIV-1 led to QUIN production while lymphocytes did not produce QUIN. The ability of the HIV-1 infected macrophages to produce QUIN was related to the viral inoculum and the degree of macrophage tropism of the isolate. The severity of ADC in the patient from whom a particular isolate was derived was not per se a determining factor for QUIN production. Purified cell free ADC isolates also led to QUIN production by macrophages thereby suggesting that HIV-1 infection alone is capable of inducing QUIN production.
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PMID:Quinolinic acid production is related to macrophage tropic isolates of HIV-1. 922 74

The hypervariable domain of the HIV gp120, the V3 loop domain, represents a target for neutralizing antibodies and for HIV vaccine strategies. In this study, we have investigated in murine species the potential cross-reactivity of immune responses elicited by immunization either with individual V3 peptides, derived from distinct HIV sequences (BRU, RF, SF2, MN and ELI sequences), or with a V3 combinatorial peptide library. We observed that individual V3 peptides are immunogenic but elicit a specific B- and T-cell immune response that is mainly restricted to the sequence of the immunizing peptide. In particular, T-cell responses that depend on T-cell receptor recognition of peptides bound to the molecules encoded by the major histocompatibility complex were significantly influenced by small differences in the peptide amino acid sequence. The combinatorial V3 peptide library, previously described as B- and T-cell immunogens, induced a more broadly reactive immune response, specially when T-cell cytokine secretion was used as a readout for restimulation of T-cells with individual V3 peptides. These data suggest that amino acid variations in the sequence of an antigenic peptide could lead to the induction of different transducing signals in the primed T-cell population and to the activation of T-cells with distinct cytokine secretion properties. These observations may have implications in the understanding of antigenic variability and in the design of vaccine strategies.
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PMID:A combinatorial peptide library around variation of the human immunodeficiency virus (HIV-1) V3 domain leads to distinct T helper cell responses. 923 25

Rhesus monkeys were successfully vaccinated using a strategy of priming with a candidate envelope subunit vaccine and boosting with synthetic peptides. Priming was carried out with recombinant HIV-1 SF2 envelope glycoprotein incorporated into ISCOMs, following the attachment of a lipid tail. Peptides, covalently linked to ISCOMs, representing linear sequences with the V2 and V3 regions, were used to boost functional antibodies-to neutralizing epitopes in both of these regions. Injections with these peptide formulations substantially increased the titre of serum neutralizing antibodies from low or undetectable levels. In addition to completely neutralizing the homologous HIV-1 SF2 strain, these sera also neutralized the escape variant, HIV-1 SF13. However, no antibodies were boosted which could compete with human, neutralizing monoclonal antibodies recognising conformational epitopes. The peptides also boosted antibodies to a peptide whose sequence lies close to the V2 region neutralizing epitope but does not overlap with it. Importantly, the level of antibodies to an unrelated epitope associated with enhancement of HIV-1 SF13 continued to fall after the peptide boost. Successful protection against challenge with chimeric simian immunodeficiency virus expressing HIV-1 SF13 envelope glycoproteins (SHIV SF13) may be due to an increase in the ratio of neutralizing to enhancing antibodies by selectively boosting with peptides to critical neutralizing epitopes.
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PMID:A recombinant prime, peptide boost vaccination strategy can focus the immune response on to more than one epitope even though these may not be immunodominant in the complex immunogen. 936 97

Nef proteins from human immunodeficiency virus type 1 isolate SF2 (HIV-1SF2) and simian immunodeficiency virus isolate mac239 (SIVmac239) have been found to associate with a cellular serine/threonine kinase designated NAK. We have recently shown that the association of Nef with NAK is isolate dependent. To identify the structural basis for Nef-kinase association, several chimeric molecules were constructed between SF2 Nef (binding NAK) and 233 Nef (a primary isolate not binding NAK) and stably expressed in HuT-78 human T cells via retrovirus-mediated gene transfer. The Nef 233/SF2/SF2 chimera in which the N-terminal 37 amino acids of SF2 Nef were replaced by those of 233 Nef showed the same ability as SF2 Nef to bind NAK. The Nef 233/SF2/233 chimera in which the N-terminal 37 amino acids and the C-terminal 72 amino acids of SF2 Nef were replaced by corresponding sequences from 233 Nef completely lost the ability to associate with the kinase activity. Furthermore, replacement of the C-terminal 72 amino acids of 233 Nef with the equivalent SF2 sequence (chimera 233/233/SF2) fully restored kinase association to 233 Nef. These results suggest that (i) the core of Nef is not sufficient for NAK binding, (ii) the C terminus of SF2 Nef contains structural determinants important for association with NAK, and (iii) the failure of 233 Nef to bind NAK is due to a defect in its C terminus. Taking advantage of the C terminus of 233 Nef being nonfunctional and using an infectious clone of HIV-1SF2, we show that association with NAK is not required for Nef-mediated infectivity enhancement. While the strong and reproducible association of some Nef isolates with NAK has been clearly established, the role of NAK in Nef function remains to be fully elucidated.
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PMID:Infectivity enhancement by human immunodeficiency virus type 1 Nef is independent of its association with a cellular serine/threonine kinase. 937 15

The splicing reaction that removes introns from pre-messenger RNAs requires the assembly of the spliceosome on the nascent transcript, proper folding of the substrate-enzyme complex, and finally, two transesterification reactions. These stages in the splicing reaction must require careful orchestration. Here we show data that suggest that the sequential phosphorylation and dephosphorylation of SR proteins mark the transition between stages in the splicing reaction. Many data had already led to the idea that phosphorylation of SR proteins could modulate their activity, when we showed that dephosphorylation of these proteins abrogates their activity in a reaction measuring conversion of pre-spliceosomes to spliceosomes (Roscigno RF, Garcia-Blanco MA, 1995, RNA 1:692-706). Subsequently, Xiao and Manley (1997, Genes & Dev 11:334-344) showed that phosphorylated ASF/SF2, but not mock-phosphorylated ASF/SF2, activates the splicing of HIV tat pre-mRNA in reactions challenged with excess random RNA. Here we confirm and extend these two findings. Phosphorylated ASF/SF2 efficiently complemented an SR protein-deficient HeLa S100 extract in promoting the splicing of an adenovirus-2-derived pre-messenger RNA, whereas unphosphorylated ASF/ SF2 did not. Moreover, we show that, whereas unphosphorylated ASF/SF2 inhibited splicing in HeLa nuclear extracts, phosphorylation of the ASF/SF2 reversed the inhibition and enhanced splicing. We also present data that shows that dephosphorylation of ASF/SF2 is required for the first transesterification reaction once the spliceosome has assembled. Thiophosphorylated ASF/SF2, which cannot be readily dephosphorylated, can promote spliceosome assembly, but cannot promote the first transesterification reaction. These data, together with other observations, indicate for the first time a requirement for SR protein dephosphorylation in pre-messenger RNA splicing in vitro.
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PMID:Both phosphorylation and dephosphorylation of ASF/SF2 are required for pre-mRNA splicing in vitro. 940 96

HIV-1 infection results in the loss of CD4+ T helper lymphocytes which make up the immune repertoire. This leads to opportunistic infections that define AIDS. Here, we show that CD4 T cell lines from normal donors with specificity for different antigens can be rendered resistant to HIV-1 replication by retroviral transduction with an antisense vector directed to the HIV-1 tat gene. The genetic treatment did not affect the properties of antigen-specific CD4 lymphocytes such as proliferative response, lymphokine production and phenotypic markers. The HIV-1 challenge dose that resulted in productive infection was two to four logs higher for transduced cells as compared with control cells. Resistance was shown with the HXB2 strain, whose tat sequence was used to design the antisense gene, and with the SF2 strain, whose targeted tat sequence carries five nucleotide mismatches. Retroviral transduction was also performed on a Candida-specific T cell line from a seropositive individual. This line, derived from T cells infected in vivo, produced infectious virus when stimulated in vitro with antigen, but was no longer productive after transduction. In addition, a four log higher HIV-1 challenge dose was needed for a productive superinfection of this T cell line. The production of antigen-specific CD4 T cells resistant to HIV-1 replication to be used in adoptive immunotherapy of opportunistic infections may represent a new form of gene therapy of AIDS.
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PMID:Anti-HIV genetic treatment of antigen-specific human CD4 lymphocytes for adoptive immunotherapy of opportunistic infections in AIDS. 942 45


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