Potential New Therapies for the Treatment of HIV-1 Infection

Condra, Jon H.; Miller, Michael D.; Hazuda, Daria J.; Emini, Emilio A.

doi:10.1146/annurev.med.53.082901.104110

Cited by 39 publications

(31 citation statements)

References 53 publications

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“…Existing classes of antiretroviral drugs act primarily by blocking steps in the virus life cycle that occur inside target cells. More recently, novel therapeutic strategies are aimed at disrupting the initial interactions between the HIV-1 gp120 and its ligands on the target cell, i.e., CD4 and the appropriate chemokine receptor (47). Given that our data indicate that galectin-1 confers HIV-1 resistance to neutralization by various agents interfering with virus attachment, it is possible that endogenous galectin-1 can reduce the anti-HIV-1 activity of newly developed entry inhibitors.…”

Section: Discussionmentioning

confidence: 94%

Galectin-1 Acts as a Soluble Host Factor That Promotes HIV-1 Infectivity through Stabilization of Virus Attachment to Host Cells

Ouellet¹,

Mercier²,

Pelletier

et al. 2005

The Journal of Immunology

155

161

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The establishment of HIV type 1 (HIV-1) infection is initiated by the stable attachment of the virion to the target cell surface. Although this process relies primarily upon interaction between virus-encoded gp120 and cell surface CD4, a number of distinct interactions influence binding of HIV-1 to host cells. In this study, we report that galectin-1, a dimeric β-galactoside-binding protein, promotes infection with R5, X4, and R5X4 variants. Galectin-1 acts as a soluble adhesion molecule by facilitating attachment of HIV-1 to the cell surface. This postulate is based on experiments where galectin-1 rendered HIV-1 particles more refractory to various agents that block HIV-1 adsorption and coreceptor binding (i.e., a blocking anti-CD4, soluble CD4, human anti-HIV-1 polyclonal Abs; stromal cell-derived factor-1α; RANTES). Experiments performed with the fusion inhibitor T-20 confirmed that galectin-1 is primarily affecting HIV-1 attachment. The relevance of the present findings for the pathogenesis of HIV-1 infection is provided by the fact that galectin-1 is abundantly expressed in the thymus and lymph nodes, organs that represent major reservoirs for HIV-1. Moreover, galectin-1 is secreted by activated CD8+ T lymphocytes, which are found in high numbers in HIV-1-positive patients. Therefore, it is proposed that galectin-1, which is released in an exocrine fashion at HIV-1 replication sites, can cross-link HIV-1 and target cells and promote a firmer adhesion of the virus to the cell surface, thereby augmenting the efficiency of the infection process. Overall, our findings suggest that galectin-1 might affect the pathogenesis of HIV-1 infection.

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Section: Discussionmentioning

confidence: 94%

Galectin-1 Acts as a Soluble Host Factor That Promotes HIV-1 Infectivity through Stabilization of Virus Attachment to Host Cells

Ouellet¹,

Mercier²,

Pelletier

et al. 2005

The Journal of Immunology

155

161

View full text Add to dashboard Cite

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“…This region represents the conformational binding domain for the neutralizing antibody 2D7 (27), which has been involved in ligand/ or virus/receptor interaction (27)(28)(29)(30). However, as occurs with other antiviral small molecules (31)(32)(33)(34), it is also plausible that compound 1 may occupy the CCR5 pocket, inducing a conformational change that may affect the second extracellular loop of CCR5, impairing its recognition by the anti-CCR5 mAb CD195 (2D7). These potential conformational changes may also affect RANTES-CCR5 binding and CCR5/ gp120-mediated R5-tropic HIV-1 viral infection.…”

Section: Discussionmentioning

confidence: 99%

The Lupane-type Triterpene 30-Oxo-calenduladiol Is a CCR5 Antagonist with Anti-HIV-1 and Anti-chemotactic Activities

Barroso-González

Jaber-Vazdekis

García-Expósito

et al. 2009

Journal of Biological Chemistry

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The existence of drug-resistant human immunodeficiency virus (HIV) viruses in patients receiving antiretroviral treatment urgently requires the characterization and development of new antiretroviral drugs designed to inhibit resistant viruses and to complement the existing antiretroviral strategies against AIDS. We assayed several natural or semi-synthetic lupane-type pentacyclic triterpenes in their ability to inhibit HIV-1 infection in permissive cells. We observed that the 30-oxo-calenduladiol triterpene, compound 1, specifically impaired R5-tropic HIV-1 envelope-mediated viral infection and cell fusion in permissive cells, without affecting X4-tropic virus. This lupane derivative competed for the binding of a specific anti-CCR5 monoclonal antibody or the natural CCL5 chemokine to the CCR5 viral coreceptor with high affinity. 30-Oxo-calenduladiol seems not to interact with the CD4 antigen, the main HIV receptor, or the CXCR4 viral coreceptor. Our results suggest that compound 1 is a specific CCR5 antagonist, because it binds to the CCR5 receptor without triggering cell signaling or receptor internalization, and inhibits RANTES (regulated on activation normal T cell expressed and secreted)-mediated CCR5 internalization, intracellular calcium mobilization, and cell chemotaxis. Furthermore, compound 1 appeared not to interact with ␤-chemokine receptors CCR1, CCR2b, CCR3, or CCR4. Thereby, the 30-oxocalenduladiol-associated anti-HIV-1 activity against R5-tropic virus appears to rely on the selective occupancy of the CCR5 receptor to inhibit CCR5-mediated HIV-1 infection. Therefore, it is plausible that the chemical structure of 30-oxo-calenduladiol or other related dihydroxylated lupane-type triterpenes could represent a good model to develop more potent anti-HIV-1 molecules to inhibit viral infection by interfering with early fusion and entry steps in the HIV life cycle. The human immunodeficiency virus (HIV)7 pandemic is a medical challenge and represents the public health crisis of our time (1-5). Antiretroviral treatment achieves long-lasting viral suppression and, subsequently, reduces the morbidity and mortality of HIV-infected individuals. However, current drugs do not eradicate HIV infection and lifelong treatment might be needed (2).Emerging drug-resistant HIV viruses, in patients receiving high active antiretroviral treatment, urgently needs the development of new antiretroviral molecules designed to inhibit resistant viruses, because many patients treated during the past decades harbor viral strains with reduced susceptibilities to many if not all available drugs (2, 6). In this matter, pentacyclic triterpenes represent a varied class of natural products presenting antitumor and antiviral activities (7-9). A well studied pentacyclic lupane-type triterpene is the betulinic acid (3␤-hydroxy-lup-20(29)-en-28-oic acid), widely distributed throughout the plant kingdom, which presents anti-inflammatory, anti-malarial, and anti-HIV-1 effects in vitro (7, 9, 10). Although its mechanism of action has not been f...

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“…Despite the effectiveness of highly active antiretroviral therapy in controlling human immunodeficiency virus type 1 (HIV-1) replication, the emergence of drug-resistant viruses in infected patients and the severe side effects caused by the currently used drug regimen necessitate continued search for new and improved therapeutic strategies for controlling AIDS (12,42). HIV-1-encoded proteins such as integrase (IN) and cellular proteins that are implicated in the HIV-1 life cycle are attractive targets for the development of antivirals (22,38).…”

mentioning

confidence: 99%

Specificity of Interaction of INI1/hSNF5 with Retroviral Integrases and Its Functional Significance

Yung

Sorin

Wang

et al. 2004

J Virol

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Integrase interactor 1 (INI1)/hSNF5 is a host factor that directly interacts with human immunodeficiency virus type 1 (HIV-1) integrase and is incorporated into HIV-1 virions. Here, we show that while INI1/hSNF5 is completely absent from purified microvesicular fractions, it is specifically incorporated into HIV-1 virions with an integrase-to-INI1/hSNF5 stoichiometry of approximately 2:1 (molar ratio). In addition, we show that INI1/hSNF5 is not incorporated into related primate lentiviral and murine retroviral particles despite the abundance of the protein in producer cells. We have found that the specificity in incorporation of INI1/hSNF5 into HIV-1 virions is directly correlated with its ability to exclusively interact with HIV-1 integrase but not with other retroviral integrases. This specificity is also reflected in our finding that the transdominant mutant S6, harboring the minimal integrase interaction domain of INI1/hSNF5, blocks HIV-1 particle production but not that of the other retroviruses in 293T cells. Taken together, these results suggest that INI1/hNSF5 is a host factor restricted for HIV-1 and that S6 acts as a highly specific and potent inhibitor of HIV-1 replication.Despite the effectiveness of highly active antiretroviral therapy in controlling human immunodeficiency virus type 1 (HIV-1) replication, the emergence of drug-resistant viruses in infected patients and the severe side effects caused by the currently used drug regimen necessitate continued search for new and improved therapeutic strategies for controlling AIDS (12, 42). HIV-1-encoded proteins such as integrase (IN) and cellular proteins that are implicated in the HIV-1 life cycle are attractive targets for the development of antivirals (22,38).IN catalyzes the integration of viral cDNA into the host genomic DNA, a process that is essential for the replication of all retroviruses and a step that results in the latent form of the virus (8). During the life cycle of a retrovirus, IN is produced as part of the Gag-Pol polyprotein, which is assembled into virions and subsequently cleaved into individual components during maturation (8). IN consists of three distinct structural domains (2), the N-terminal zinc-binding domain (HHCC), the central core domain with a highly conserved D,D(35)E motif required for the catalytic activity, and the less highly conserved C-terminal domain. Although crystal structure data exist for single and double domains of IN, no structural data exist yet for the entire IN protein (18). Various biochemical and genetic approaches have been used to demonstrate the multimerization of IN (1, 16, 25), but the exact nature of the IN multimer is still unknown (11,24).Studies of IN have demonstrated that it may affect steps in viral replication besides integration itself. For example, the presence of IN mutations affects viral morphology, particle formation, particle release, and infectivity (9, 17, 43). Deletions or mutations in the Zn finger region of IN (for example, H12A) have been shown to result in decreased parti...

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Potential New Therapies for the Treatment of HIV-1 Infection

Cited by 39 publications

References 53 publications

Galectin-1 Acts as a Soluble Host Factor That Promotes HIV-1 Infectivity through Stabilization of Virus Attachment to Host Cells

Galectin-1 Acts as a Soluble Host Factor That Promotes HIV-1 Infectivity through Stabilization of Virus Attachment to Host Cells

The Lupane-type Triterpene 30-Oxo-calenduladiol Is a CCR5 Antagonist with Anti-HIV-1 and Anti-chemotactic Activities

Specificity of Interaction of INI1/hSNF5 with Retroviral Integrases and Its Functional Significance

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