Cocaine and  -1 receptors modulate HIV infection, chemokine receptors, and the HPA axis in the huPBL-SCID model

2005 ◽  
Vol 78 (6) ◽  
pp. 1198-1203 ◽  
Author(s):  
M. D. Roth
Keyword(s):  
Hiv Infection ◽  
Hpa Axis ◽  
Chemokine Receptors

scholarly journals Structure/Function Studies Involving the V3 Region of the HIV-1 Envelope Delineate Multiple Factors That Affect Neutralization Sensitivity

2015 ◽  
Vol 90 (2) ◽  
pp. 636-649 ◽  
Author(s):  
Susan Zolla-Pazner ◽  
Sandra Sharpe Cohen ◽  
David Boyd ◽  
Xiang-Peng Kong ◽  
Michael Seaman ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hiv Infection ◽  
Chemokine Receptors ◽  
Variable Region ◽  
Single Amino Acid ◽  
V3 Loop ◽  
Infection Rates ◽  
Neutralization Sensitivity ◽  
The Stability ◽  
Hiv 1

ABSTRACTAntibodies (Abs) specific for the V3 loop of the HIV-1 gp120 envelope neutralize most tier 1 and many tier 2 viruses and are present in essentially all HIV-infected individuals as well as immunized humans and animals. Vaccine-induced V3 Abs are associated with reduced HIV infection rates in humans and affect the nature of transmitted viruses in infected vaccinees, despite the fact that V3 is often occluded in the envelope trimer. Here, we link structural and experimental data showing how conformational alterations of the envelope trimer render viruses exceptionally sensitive to V3 Abs. The experiments interrogated the neutralization sensitivity of pseudoviruses with single amino acid mutations in various regions of gp120 that were predicted to alter packing of the V3 loop in the Env trimer. The results indicate that the V3 loop is metastable in the envelope trimer on the virion surface, flickering between states in which V3 is either occluded or available for binding to chemokine receptors (leading to infection) and to V3 Abs (leading to virus neutralization). The spring-loaded V3 in the envelope trimer is easily released by disruption of the stability of the V3 pocket in the unliganded trimer or disruption of favorable V3/pocket interactions. Formation of the V3 pocket requires appropriate positioning of the V1V2 domain, which is, in turn, dependent on the conformation of the bridging sheet and on the stability of the V1V2 B-C strand-connecting loop.IMPORTANCEThe levels of antibodies to the third variable region (V3) of the HIV envelope protein correlate with reduced HIV infection rates. Previous studies showed that V3 is often occluded, as it sits in a pocket of the envelope trimer on the surface of virions; however, the trimer is flexible, allowing occluded portions of the envelope (like V3) to flicker into an exposed position that binds antibodies. Here we provide a systematic interrogation of mechanisms by which single amino acid changes in various regions of gp120 (i) render viruses sensitive to neutralization by V3 antibodies, (ii) result in altered packing of the V3 loop, and (iii) activate an open conformation that exposes V3 to the effects of V3 Abs. Taken together, these and previous studies explain how V3 antibodies can protect against HIV-1 infection and why they should be one of the targets of vaccine-induced antibodies.

Interferon-γ Upregulates CCR5 Expression in Cord and Adult Blood Mononuclear Phagocytes

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1137-1144 ◽  
Author(s):  
Deepa Hariharan ◽  
Steven D. Douglas ◽  
Benhur Lee ◽  
Jian-Ping Lai ◽  
Donald E. Campbell ◽  
...  
Keyword(s):  
Cell Surface ◽  
Hiv Infection ◽  
Chemokine Receptors ◽  
Surface Expression ◽  
Interferon Γ ◽  
Mononuclear Phagocytes ◽  
Cell Surface Expression ◽  
Ccr5 Expression ◽  
Hiv Entry ◽  
Ifn Γ

Abstract The C-C chemokine receptors CCR5 and CCR3 are fusion coreceptors for human immunodeficiency virus (HIV) entry into macrophages. The regulation of their expression influences infectivity by HIV. We report here that interferon-γ (IFN-γ) a cytokine that has bidirectional effects on HIV infection of macrophages, significantly upregulated CCR5 and CCR3 cell surface expression in human mononuclear phagocytes isolated from placental cord blood and adult peripheral blood. Monocytes treated with IFN-γ showed increased chemotaxis to the CCR5 ligands macrophage inflammatory protein-1 (MIP-1) and MIP-1β, confirming the functional relevance of IFN-γ–induced CCR5 expression. However, IFN-γ suppressed HIV entry into macrophages. Interestingly, we demonstrated that IFN-γ inhibited cell surface expression of CD4, the major receptor for HIV. This finding may explain the suppressive effect of IFN-γ on HIV entry into macrophages, despite its enhancing effect on the expression of CCR5 and CCR3 by these cells. In addition, IFN-γ–induced secretion of C-C chemokines (RANTES, MIP-1, and MIP-1β) by mononuclear phagocytes may also suppress HIV entry into macrophages. These data provide further evidence for cytokine-mediated regulation of CCR5 expression and are consistent with a novel paradigm in which cytokines regulate HIV infection and leukocyte migration by reciprocal and opposing effects on the expression of CD4 and chemokine receptors.

Antiretroviral agents: Focus on Maraviroc for the Treatment of HIV-1-Infected Adults

2010 ◽  
Vol 2 ◽  
pp. CMT.S5420
Author(s):  
SL. Pett ◽  
S. Emery ◽  
AD. Kelleher ◽  
DA. Cooper
Keyword(s):  
Hiv Infection ◽  
Chemokine Receptors ◽  
Hiv Transmission ◽  
Hiv Therapy ◽  
Ccr5 Receptor ◽  
Tick Borne Encephalitis ◽  
Hiv Entry ◽  
Orally Bioavailable ◽  
Hiv Envelope ◽  
Hiv 1

Over a decade has passed since several groups identified the chemokine receptors CXCR4 and CCR5 as key co-receptors for HIV entry. CCR5 is more important in HIV transmission and during the early course of HIV infection. It is also apparent that protection from HIV infection is afforded to those lacking CCR5–-the so called delta-32 homozygotes; in those heterozygous for this mutation, an attenuated course of HIV-infection is observed. Provocatively, those with modified expression of CCR5 are physiologically normal with the exception of poorer outcomes with some of the viral encephalitides specifically West Nile virus and Tick Borne encephalitis. The small molecule, orally-bioavailable CCR5 receptor antagonists, including, maraviroc (MVC), are allosteric inhibitors that lock the CCR5 receptor into a conformation such that the receptor is not able to bind HIV envelope protein; the molecules also variably block intracellular signalling induced by different receptor-binding chemokines. The aims of this review on the CCR5 receptor inhibitors are to summarise information relevant to treatment in individuals with HIV-1 infection. Data from the licensing studies, the side-effect profile and putative long-term risks of CCR5 receptor inhibitor exposure, tropism testing and mechanisms of resistance will be reviewed. The potential for using this class of agent as an immunomodulating agent will be detailed. Given that MVC is the only licensed drug in this class at present and reflecting the greater body of work describing this agent, the majority of information in this review relates to MVC. Last, the authors propose the place of MVC in the hierarchy of HIV therapy and future opportunities for research.

scholarly journals Expression of Human CD4 and chemokine receptors in cotton rat cells confers permissiveness for productive HIV infection

2009 ◽  
Vol 6 (1) ◽  
pp. 57 ◽  
Author(s):  
Jorge CG Blanco ◽  
Lioubov M Pletneva ◽  
Lindsay Wieczorek ◽  
Dimple Khetawat ◽  
Tzanko S Stantchev ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Chemokine Receptors ◽  
Cotton Rat

Curdlan Sulfate Induces the Downmodulation of Chemokine Receptors Leading to Suppression of HIV Infection

2001 ◽  
Vol 26 (5) ◽  
pp. 512-513 ◽  
Author(s):  
Toshio Naito ◽  
Makiko Okada ◽  
Hitoshi Ogasawara ◽  
Hiroshi Kaneko ◽  
Takashi Hishikawa ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Chemokine Receptors

Defensins and Chemokine receptors: Protecting highly susceptible cells from HIV infection by inducing APOBEC3G expression

2011 ◽  
Vol 02 (01) ◽  
Author(s):  
Alfredo Garzino-Demo ◽  
Mark K. Lafferty ◽  
Jennifer Bharucha ◽  
Lingling Sun ◽  
Walter Roya
Keyword(s):  
Hiv Infection ◽  
Chemokine Receptors ◽  
Apobec3g Expression

scholarly journals Anti-HIV Agent Trichosanthin Enhances the Capabilities of Chemokines to Stimulate Chemotaxis and G Protein Activation, and This Is Mediated through Interaction of Trichosanthin and Chemokine Receptors

1999 ◽  
Vol 190 (1) ◽  
pp. 101-112 ◽  
Author(s):  
Jian Zhao ◽  
Li-Hong Ben ◽  
Ya-Lan Wu ◽  
Wei Hu ◽  
Kun Ling ◽  
...  
Keyword(s):  
Hiv Infection ◽  
G Protein ◽  
Chemokine Receptors ◽  
Hek293 Cells ◽  
Chinese Medicinal Herb ◽  
Protein Activation ◽  
G Protein Activation ◽  
Trichosanthes Kirilowii ◽  
Stromal Cell Derived Factor ◽  
Specific Association

Trichosanthin (TCS), an active protein component isolated from a traditional Chinese medicinal herb Trichosanthes kirilowii, has been shown to inhibit HIV infection and has been applied in clinical treatment of AIDS. The recent development that chemokines and chemokine receptors play important roles in HIV infection led us to investigate the possible functional interaction of TCS with chemokines and their receptors. This study demonstrated that TCS greatly enhanced both RANTES (regulated upon activation, normal T cell expressed and secreted)– and stromal cell–derived factor (SDF)-1α–stimulated chemotaxis (EC50 ≅ 1 nM) in leukocytes (THP-1, Jurkat, and peripheral blood lymphocyte cells) and activation of pertussis toxin–sensitive G proteins (EC50 ≅ 20 nM). TCS also significantly augmented chemokine-stimulated activation of chemokine receptors CCR5 and CXCR4 as well as CCR1, CCR2B, CCR3, and CCR4 transiently expressed in HEK293 cells. A mutant TCS with 4,000-fold lower ribosome-inactivating activity showed similar augmentation activity as wild-type TCS. Moreover, flow cytometry demonstrated that the specific association of TCS to the cell membranes required the presence of chemokine receptors, and laser confocal microscopy reveals that TCS was colocalized with chemokine receptors on the membranes. The results from TCS-Sepharose pull-down and TCS and chemokine receptor coimmunoprecipitation and cross-linking experiments demonstrated association of TCS with CCR5. Thus, our data clearly demonstrated that TCS synergizes activities of chemokines to stimulate chemotaxis and G protein activation, and the effects of TCS are likely to be mediated through its interaction with chemokine receptors.

The HPA Axis and HIV Infection

2001 ◽  
pp. 317-327
Author(s):  
Daniel S. Donovan ◽  
Robert G. Dluhy
Keyword(s):  
Hiv Infection ◽  
Hpa Axis

CCR5 Antagonists: Host-Targeted Antivirals for the Treatment of HIV Infection

2005 ◽  
Vol 16 (6) ◽  
pp. 339-354 ◽  
Author(s):  
Mike Westby ◽  
Elna van der Ryst
Keyword(s):  
Hiv Infection ◽  
Small Molecule ◽  
Chemokine Receptors ◽  
Ccr5 Gene ◽  
Sexually Transmitted ◽  
New Class ◽  
Ccr5 Antagonists ◽  
Resistance To Infection ◽  
Plasma Half Life ◽  
Hiv 1

The human chemokine receptors, CCR5 and CXCR4, are potential host targets for exogenous, small-molecule antagonists for the inhibition of HIV-1 infection. HIV-1 strains can be categorised by co-receptor tropism — their ability to utilise CCR5 (CCR5-tropic), CXCR4 (CXCR4-tropic) or both (dual-tropic) as a co-receptor for entry into susceptible cells. CCR5 may be the more suitable co-receptor target for small-molecule antagonists because a natural deletion in the CCR5 gene preventing its expression on the cell surface is not associated with any obvious phenotype, but can confer resistance to infection by CCR5-tropic strains — the most frequently sexually-transmitted strains. The current leading CCR5 antagonists in clinical development include maraviroc (UK-427,857, Pfizer), aplaviroc (873140, GlaxoSmithKline) and vicriviroc (SCH-D, Schering-Plough), which have demonstrated efficacy and tolerability in HIV-infected patients. Pharmacodynamic data also suggest that these compounds have a long plasma half-life and/or prolonged CCR5 occupancy, which may explain the delay in viral rebound observed following compound withdrawal in short-term monotherapy studies. A switch from CCR5 to CXCR4 tropism occurs spontaneously in approximately 50% of HIV-infected patients and has been associated with, but is not required for, disease progression. The possibility of a co-receptor tropism switch occurring under selection pressure by CCR5 antagonists is discussed. The completion of ongoing Phase IIb/III studies of maraviroc, aplaviroc and vicriviroc will provide further insight into co-receptor tropism, HIV pathogenesis and the suitability of CCR5 antagonists as a potent new class of antivirals for the treatment of HIV infection.

E3 Inhibition of HIV Infection in Highly Susceptible Cells With Human β-Defensins—Induction of APOBEC3G Via Chemokine Receptors

2012 ◽  
Vol 59 ◽  
pp. 83
Author(s):  
Mark K. Lafferty ◽  
Jennifer Bharucha ◽  
Olga Latinovic ◽  
Lingling Sun ◽  
Walter Royal ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Chemokine Receptors
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