Current Peptide HIV Type-1 Fusion Inhibitors

2009 ◽  
Vol 20 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Wei Pang ◽  
Siu-Cheung Tam ◽  
Yong-Tang Zheng
Keyword(s):  
Antiviral Agents ◽  
Antiretroviral Drugs ◽  
Host Cells ◽  
Fixed Dose ◽  
Clinical Use ◽  
The Past ◽  
Fusion Inhibitors ◽  
Hiv Type 1 ◽  
Hiv 1

There are now 26 antiretroviral drugs and 6 fixed-dose combinations, including reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and fusion (or entry) inhibitors, approved by the US Food and Drug Administration for clinical use. Although they are clinically effective when used in combination, none of the existing drugs are considered ideal because of toxic side effects and the ascendance of inducing drug-resistant mutants. Development of new antiviral agents is essential. In the past decades, there has been great progress in understanding the structure of HIV type-1 (HIV-1) gp41 and the mechanism of HIV-1 entry into host cells. This opened up a promising avenue for rationally designed agents to interfere with this process. A number of fusion inhibitors have been developed to block HIV-1 replication. Enfuvirtide (T20) was one of those approved for clinical use. This signalled a new era in AIDS therapeutics. It is a synthetic polypeptide with potent inhibitory activity against HIV-1 infection. However, it is sensitive to proteolytic digestion and resistant virus strains are easily induced with multiple clinical use. One of the directions in designing new fusion inhibitors is to overcome these shortages. In the past years, large numbers of promising fusion inhibitory peptides have emerged. The antiviral activities are more potent or they can act differently from that of T20. Some of these new compounds have great potential to be further developed as therapeutic agents. This article reviewed some recent developments of these peptides and the possible role in anti-HIV-1 therapy.

scholarly journals Combinations of the First and Next Generations of Human Immunodeficiency Virus (HIV) Fusion Inhibitors Exhibit a Highly Potent Synergistic Effect against Enfuvirtide- Sensitive and -Resistant HIV Type 1 Strains

2009 ◽  
Vol 83 (16) ◽  
pp. 7862-7872 ◽  
Author(s):  
Chungen Pan ◽  
Lifeng Cai ◽  
Hong Lu ◽  
Zhi Qi ◽  
Shibo Jiang
Keyword(s):  
Human Immunodeficiency Virus ◽  
Synergistic Effect ◽  
First Generation ◽  
Antiretroviral Drugs ◽  
Synergistic Activity ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Hiv 1

ABSTRACT T20 (generic name, enfuvirtide; brand name, Fuzeon) is a first-generation human immunodeficiency virus (HIV) fusion inhibitor approved for salvage therapy of HIV-infected patients refractory to current antiretroviral drugs. However, its clinical use is limited because of rapid emergence of T20-resistant viruses in T20-treated patients. Therefore, T1249 and T1144 are being developed as the second- and third-generation HIV fusion inhibitors, respectively, with improved efficacy and drug resistance profiles. Here, we found that combinations of T20 with T1249 and/or T1144 resulted in exceptionally potent synergism (combination index, <0.01) against HIV-1-mediated membrane fusion by 2 to 3 orders of magnitude in dose reduction. Highly potent synergistic antiviral efficacy was also achieved against infection by laboratory-adapted and primary HIV-1 strains, including T20-resistant variants. The mechanism underlying the synergistic effect could be attributed to the fact that T20, T1249, and T1144 all contain different functional domains and have different primary binding sites in gp41. As such, they may work cooperatively to inhibit gp41 six-helix bundle core formation, thereby suppressing virus-cell fusion. Therefore, these findings strongly imply that, rather than replacing T20, combining it with HIV fusion inhibitors of different generations might produce synergistic activity against both T20-sensitive and -resistant HIV-1 strains, suggesting a new therapeutic strategy for the treatment of HIV-1 infection/AIDS.

scholarly journals Lentiviral Nef Proteins Utilize PAK2-Mediated Deregulation of Cofilin as a General Strategy To Interfere with Actin Remodeling

2010 ◽  
Vol 84 (8) ◽  
pp. 3935-3948 ◽  
Author(s):  
Bettina Stolp ◽  
Libin Abraham ◽  
Jochen M. Rudolph ◽  
Oliver T. Fackler
Keyword(s):  
Host Cells ◽  
General Strategy ◽  
Actin Remodeling ◽  
Mechanistic Analysis ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Hiv 1

ABSTRACT Nef is an accessory protein and pathogenicity factor of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) which elevates virus replication in vivo. We recently described for HIV type 1SF2 (HIV-1SF2) the potent interference of Nef with T-lymphocyte chemotaxis via its association with the cellular kinase PAK2. Mechanistic analysis revealed that this interaction results in deregulation of the actin-severing factor cofilin and thus blocks the chemokine-mediated actin remodeling required for cell motility. However, the efficiency of PAK2 association is highly variable among Nef proteins from different lentiviruses, prompting us to evaluate the conservation of this actin-remodeling/cofilin-deregulating mechanism. Based on the analysis of a total of 17 HIV-1, HIV-2, and SIV Nef proteins, we report here that inhibition of chemokine-induced actin remodeling as well as inactivation of cofilin are strongly conserved activities of lentiviral Nef proteins. Of note, even for Nef variants that display only marginal PAK2 association in vitro, these activities require the integrity of a PAK2 recruitment motif and the presence of endogenous PAK2. Thus, reduced in vitro affinity to PAK2 does not indicate limited functionality of Nef-PAK2 complexes in intact HIV-1 host cells. These results establish hijacking of PAK2 for deregulation of cofilin and inhibition of triggered actin remodeling as a highly conserved function of lentiviral Nef proteins, supporting the notion that PAK2 association may be critical for Nef's activity in vivo.

Anatomy and pathology of HIV-1 peptidase

2002 ◽  
Vol 38 ◽  
pp. 113-127 ◽  
Author(s):  
Ben M Dunn
Keyword(s):  
Feline Immunodeficiency Virus ◽  
Drug Target ◽  
Concerted Effort ◽  
Drug Pressure ◽  
The Past ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Hiv 1

The peptidase of the HIV type 1 (HIV PR) is required for the replication of and further infection by the virus. A concerted effort has taken place in the past 15 years to understand the properties of this enzyme, as it serves as an excellent drug target for control of the virus. Owing to drug pressure, many mutations arise during turnover of the virus and some of these lead to resistance to the effects of the inhibitors. Recent advances in the understanding of the changes these mutations cause to the enzyme and its interaction with substrates and inhibitors have been described. In addition, studies of closely related retroviral enzymes from simian immunodeficiency virus, feline immunodeficiency virus and HIV-2 have expanded the structure-function paradigm. The role of the flexibility of ligands and of the enzyme in active-site interactions is discussed.

scholarly journals Contribution of Immune Activation to the Pathogenesis and Transmission of Human Immunodeficiency Virus Type 1 Infection

2001 ◽  
Vol 14 (4) ◽  
pp. 753-777 ◽  
Author(s):  
Stephen D. Lawn ◽  
Salvatore T. Butera ◽  
Thomas M. Folks
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immune Activation ◽  
Antiretroviral Drugs ◽  
Host Cells ◽  
Immunodeficiency Virus ◽  
Hiv 1

SUMMARY The life cycle of human immunodeficiency virus type 1 (HIV-1) is intricately related to the activation state of the host cells supporting viral replication. Although cellular activation is essential to mount an effective host immune response to invading pathogens, paradoxically the marked systemic immune activation that accompanies HIV-1 infection in vivo may play an important role in sustaining phenomenal rates of HIV-1 replication in infected persons. Moreover, by inducing CD4+ cell loss by apoptosis, immune activation may further be central to the increased rate of CD4+ cell turnover and eventual development of CD4+ lymphocytopenia. In addition to HIV-1-induced immune activation, exogenous immune stimuli such as opportunistic infections may further impact the rate of HIV-1 replication systemically or at localized anatomical sites. Such stimuli may also lead to genotypic and phenotypic changes in the virus pool. Together, these various immunological effects on the biology of HIV-1 may potentially enhance disease progression in HIV-infected persons and may ultimately outweigh the beneficial aspects of antiviral immune responses. This may be particularly important for those living in developing countries, where there is little or no access to antiretroviral drugs and where frequent exposure to pathogenic organisms sustains a chronically heightened state of immune activation. Moreover, immune activation associated with sexually transmitted diseases, chorioamnionitis, and mastitis may have important local effects on HIV-1 replication that may increase the risk of sexual or mother-to-child transmission of HIV-1. The aim of this paper is to provide a broad review of the interrelationship between immune activation and the immunopathogenesis, transmission, progression, and treatment of HIV-1 infection in vivo.

scholarly journals Novel TRIM5 Isoforms Expressed by Macaca nemestrina

2007 ◽  
Vol 81 (22) ◽  
pp. 12210-12217 ◽  
Author(s):  
Greg Brennan ◽  
Yury Kozyrev ◽  
Toshiaki Kodama ◽  
Shiu-Lok Hu
Keyword(s):  
Coiled Coil ◽  
Macaca Nemestrina ◽  
Cdna Clones ◽  
Reading Frame ◽  
Spry Domain ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Hiv 1

ABSTRACT The TRIM5 family of proteins contains a RING domain, one or two B boxes, and a coiled-coil domain. The TRIM5α isoform also encodes a C-terminal B30.2(SPRY) domain, differences within which define the breadth and potency of TRIM5α-mediated retroviral restriction. Because Macaca nemestrina animals are susceptible to some human immunodeficiency virus (HIV) isolates, we sought to determine if differences exist in the TRIM5 gene and transcripts of these animals. We identified a two-nucleotide deletion (Δ2) in the transcript at the 5′ terminus of exon 7 in all M. nemestrina TRIM5 cDNA clones examined. This frameshift results in a truncated protein of 300 amino acids lacking the B30.2(SPRY) domain, which we have named TRIM5θ. This deletion is likely due to a single nucleotide polymorphism that alters the 3′ splice site between intron 6 and exon 7. In some clones, a deletion of the entire 27-nucleotide exon 7 (Δexon7) resulted in the restoration of the TRIM5 open reading frame and the generation of another novel isoform, TRIM5η. There are 18 amino acid differences between M. nemestrina TRIM5η and Macaca mulatta TRIM5α, some of which are at or near locations previously shown to affect the breadth and potency of TRIM5α-mediated restriction. Infectivity assays performed on permissive CrFK cells stably transduced with TRIM5η or TRIM5θ show that these isoforms are incapable of restricting either HIV type 1 (HIV-1) or simian immunodeficiency virus infection. The expression of TRIM5 alleles incapable of restricting HIV-1 infection may contribute to the previously reported increased susceptibility of M. nemestrina to HIV-1 infection in vivo.

Neuropsychological studies of asymptomatic Human Immunodeficiency Virus-Type-1 infected individuals

1995 ◽  
Vol 1 (3) ◽  
pp. 304-315 ◽  
Author(s):  
Desirée A. White ◽  
Robert K. Heaton ◽  
Andreas U. Monsch ◽  
Keyword(s):  
Test Battery ◽  
Neuropsychological Impairment ◽  
Ongoing Debate ◽  
Immunodeficiency Virus ◽  
Type Test ◽  
Hiv Type 1 ◽  
Hiv 1 ◽  
Asymptomatic Human Immunodeficiency Virus ◽  
Asymptomatic Hiv

AbstractThe current review was conducted to address the ongoing debate regarding the presence or absence of neuropsychological impairment in asymptomatic HIV-Type 1 (HIV-1) seropositive individuals. Results were summarized from 57 studies that compared the performances of seropositive asymptomatic and seronegative individuals. Overall, the differences observed between median rates of impairment for asymptomatic (35%) and seronegative (12%) groups provided the clearest indication of deficits in asymptomatics. In addition, five variables were examined as possible contributors to inconsistencies found in the literature: mode of infection, test battery type, test battery size, sample size, and method of data analysis. Of these variables, only mode of infection and test battery size appeared to substantially influence the outcome of the studies reviewed with regard to identifying neuropsychological impairment in asymptomatics. (JINS, 1995, I, 304–315.)

scholarly journals Membrane-Anchored Peptide Inhibits Human Immunodeficiency Virus Entry

2001 ◽  
Vol 75 (6) ◽  
pp. 3038-3042 ◽  
Author(s):  
Markus Hildinger ◽  
Matthias T. Dittmar ◽  
Patricia Schult-Dietrich ◽  
Boris Fehse ◽  
Barbara S. Schnierle ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Helper ◽  
Immunodeficiency Virus ◽  
Retrovirus Vector ◽  
Human Immunodeficiency Virus Entry ◽  
Hiv Type 1 ◽  
Heptad Repeats ◽  
Hiv 1 ◽  
Gp41 Envelope

ABSTRACT Peptides derived from the heptad repeats of human immunodeficiency virus (HIV) gp41 envelope glycoprotein, such as T20, can efficiently inhibit HIV type 1 (HIV-1) entry. In this study, replication of HIV-1 was inhibited more than 100-fold in a T-helper cell line transduced with a retrovirus vector expressing membrane-anchored T20 on the cell surface. Inhibition was independent of coreceptor usage.

Sign in / Sign up

Export Citation Format

Share Document