Anti-idiotypic Antibody to the V3 Domain of gp120 Binds to Vimentin: A Possible Role of Intermediate Filaments in the Early Steps of HIV-1 Infection Cycle

Thomas, Elaine K.; Connelly, Roberta J.; Sridhar, P.; Dubrovsky, Larisa; Haffar, Omar K.; Bukrinsky, Michael

doi:10.1089/vim.1996.9.73

Cited by 31 publications

(33 citation statements)

References 58 publications

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“…Our proteomic studies found specific luteal-phase-overexpressed proteins that might be involved in enhancing HIV-1 infection: moesin (39), cathepsin G (40, 41), myeloperoxidase isoform (42), an isoform of heterogeneous nuclear ribonucleoproteins C1/C2 (43), vimentin (44), and kallikreins (45,46). Interestingly, cathepsin G, a protease, is known to be inhibited by the follicular phase-overexpressed serpins (reviewed in reference 47), which alludes to a fine balance between proteases and antiproteases in the two menstrual phases, an aspect critical to the innate mucosal immune response.…”

Section: Discussionmentioning

confidence: 97%

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

Vishwanathan

Burgener

Bosinger

et al. 2015

J Virol

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Our earlier studies with pig-tailed macaques demonstrated various simian-human immunodeficiency virus (SHIV) susceptibilities during the menstrual cycle, likely caused by cyclic variations in immune responses in the female genital tract. There is concern that high-dose, long-lasting, injectable progestin-based contraception could mimic the high-progesterone luteal phase and predispose women to human immunodeficiency type 1 (HIV-1) acquisition and transmission. In this study, we adopted a systems biology approach employing proteomics (tandem mass spectrometry), transcriptomics (RNA microarray hybridization), and other specific protein assays (enzyme-linked immunosorbent assays and multiplex chemokine and cytokine measurements) to characterize the effects of hormonal changes on the expression of innate factors and secreted proteins in the macaque vagina. Several antiviral factors and pathways (including acute-phase response signaling and complement system) were overexpressed in the follicular phase. Conversely, during the luteal phase there were factors overexpressed (including moesins, syndecans, and integrins, among others) that could play direct or indirect roles in enhancing HIV-1 infection. Thus, our study showed that specific pathways and proteins or genes might work in tandem to regulate innate immunity, thus fostering further investigation and future design of approaches to help counter HIV-1 acquisition in the female genital tract. IMPORTANCEHIV infection in women is poorly understood. High levels of the hormone progesterone may make women more vulnerable to infection. This could be the case during the menstrual cycle, when using hormone-based birth control, or during pregnancy. The biological basis for increased HIV vulnerability is not known. We used an animal model with high risk for infection during periods of high progesterone. Genital secretions and tissues during the menstrual cycle were studied. Our goal was to identify biological factors upregulated at high progesterone levels, and we indeed show an upregulation of genes and proteins which enhance the ability of HIV to infect when progesterone is high. In contrast, during low-progesterone periods, we found more HIV inhibitory factors. This study contributes to our understanding of mechanisms that may regulate HIV infection in females under hormonal influences. Such knowledge is needed for the development of novel prevention strategies. F emale acquisition of human immunodeficiency virus type 1 (HIV-1) is not an efficient process, and transmission events are estimated to occur at frequencies of 1/100 to 1/1,000 exposures (1; reviewed in reference 2). Despite this, the heterosexual route is the predominant mode of HIV-1 transmission worldwide (3), and the development of strategies to reduce male-to-female vaginal transmission rates remains a priority. Animal studies have demonstrated that the time between vaginal exposure and virus detection in draining lymph nodes is as little as 1 to 3 days. There is a small window of early protection whe...

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Section: Discussionmentioning

confidence: 97%

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

Vishwanathan

Burgener

Bosinger

et al. 2015

J Virol

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“…Although TFP/p6 pol lies outside (and upstream) of the protease, the EDL tripeptide of this cleavage site (ENL in the case of C viruses) has been postulated to have a major influence on protease activation and on the timing and specificity of GagPol cleavage, delaying the release of the protease until after the viral particle has budded from the cell membrane. Such a mechanism may protect the cell from the cytotoxic effects of proteolysis (36,38). The observed subtype variation in the cleavage sites controlling the initiation and rate of Gag and Gag-Pol processing (p2/NC) and the activation of protease (TFP/p6 gag ) suggests that there may be important differences in the way that B and C viruses regulate polyprocessing and virion assembly.…”

Section: Discussionmentioning

confidence: 99%

Variability at Human Immunodeficiency Virus Type 1 Subtype C Protease Cleavage Sites: an Indication of Viral Fitness?

Oliveira

Engelbrecht

Rensburg

et al. 2003

J Virol

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Naturally occurring polymorphisms in the protease of human immunodeficiency virus type 1 (HIV-1) subtype C would be expected to lead to adaptive (compensatory) changes in protease cleavage sites. To test this hypothesis, we examined the prevalences and patterns of cleavage site polymorphisms in the Gag, Gag-Pol, and Nef cleavage sites of C compared to those in non-C subtypes. Codon-based maximum-likelihood methods were used to assess the natural selection and evolutionary history of individual cleavage sites. Seven cleavage sites (p17/p24, p24/p2, NC/p1, NC/TFP, PR/RT, RT/p66, and p66/IN) were well conserved over time and in all HIV-1 subtypes. One site (p1/p6 gag ) exhibited moderate variation, and four sites (p2/NC, TFP/p6 pol , p6 pol /PR, and Nef) were highly variable, both within and between subtypes. Three of the variable sites are known to be major determinants of polyprotein processing and virion production. P2/NC controls the rate and order of cleavage, p6gag is an important phosphoprotein required for virion release, and TFP/p6 pol , a novel cleavage site in the transframe domain, influences the specificity of Gag-Pol processing and the activation of protease. Overall, 58.3% of the 12 HIV-1 cleavage sites were significantly more diverse in C than in B viruses. When analyzed as a single concatenated fragment of 360 bp, 96.0% of group M cleavage site sequences fell into subtype-specific phylogenetic clusters, suggesting that they coevolved with the virus. Natural variation at C cleavage sites may play an important role, not only in regulation of the viral cycle but also in disease progression and response to therapy.

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“…USA 93 (1996) 11861 like core but are composed exclusively of Gag (MA, CA, NC, and p6) and Env (gp4l and gp120) proteins (19). These pseudovirions package HIV-1 gag RNA and, as we have shown recently (26), translocate this RNA into the nucleus of an infected cell in a manner similar to the behavior of HIV-1 preintegration complexes. Results presented in Fig.…”

Section: Methodsmentioning

confidence: 75%

“…Beads were then pelleted by centrifugation and washed three times with PBS supplemented with 0.1% Tween 20, 1 ,ug/ml each of leupeptin and aprotinin, and 1 mM PMSF. HIV-1 DNA was isolated from the beads by SDS/proteinase K treatment with subsequent phenol-chloroform extraction, as described (22) (26). To control for possible differences in cell entry of wild-type versus mutant agents, HIV-specific nucleic acids were extracted directly from cytoplasmic extracts and assayed by RT-PCR (lanes 4 Proc.…”

Section: Methodsmentioning

confidence: 99%

Critical role of reverse transcriptase in the inhibitory mechanism of CNI-H0294 on HIV-1 nuclear translocation.

Попов¹,

Dubrovsky²,

Lee³

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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HIV-1 replication requires the translocation of viral genome into the nucleus of a target cell. We recently reported the synthesis of an arylene bis(methyl ketone) compound (CNI-H0294) that inhibits nuclear targeting of the HIV-1 genome and thus HIV-1 replication in monocyte cultures. Here we demonstrate that CNI-H0294 inhibits nuclear targeting of HIV-1-derived preintegration complexes by inactivating the nuclear localization sequence of the HIV-1 matrix antigen in a reaction that absolutely requires reverse transcriptase. This drug/reverse transcriptase interaction defines the specificity of its antiviral effect and is most likely mediated by the pyrimidine side-chain of CNI-H0294. After binding to reverse transcriptase, the carbonyl groups of CNI-H0294 react with the nuclear localization sequence of matrix antigen and prevent its binding to karyopherin a, the cellular receptor for nuclear localization sequences that carries proteins into the nucleus. Our results provide a basis for the development of a novel class of compounds that inhibit nuclear translocation and that can, in principle, be modified to target specific infectious agents.

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Anti-idiotypic Antibody to the V3 Domain of gp120 Binds to Vimentin: A Possible Role of Intermediate Filaments in the Early Steps of HIV-1 Infection Cycle

Cited by 31 publications

References 58 publications

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

Variability at Human Immunodeficiency Virus Type 1 Subtype C Protease Cleavage Sites: an Indication of Viral Fitness?

Critical role of reverse transcriptase in the inhibitory mechanism of CNI-H0294 on HIV-1 nuclear translocation.

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