New Therapies To Combat Hiv Biology Essay

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It has been over 25 years since what would be known as AIDS was first recognized. From last 2 decades, HIV is under continues global focus and investment. Two different types of HIV, HIV-1 and HIV-2, cause infection and disease in humans. HIV-1 is thought to have arisen from cross-species transmission of a chimpanzee virus to humans and HIV-2 from cross-species transmission of a Sooty mangabey virus. Compared to HIV-1, HIV-2 infection is characterized by a much longer asymptomatic stage, lower plasma viral load, slower decline in CD4-T cell count, and lower mortality rate attributable to AIDS. So, the major focus of research is on HIV-1 because of its more virility. The cumulative total of individuals infected with HIV-1 and deaths due to AIDS since the pandemic began exceeds 60 million and 25 million people, respectively. At the end of 2007, the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the WHO estimated that there were 33.2 million people living with HIV, that 2.5 million individuals became newly infected with HIV in 2007, and that 2.1 million people died of AIDS in that year.

The armamentarium, which is used to combat human immunodeficiency virus type 1 (HIV-1) infection, includes antiretroviral agents drawn from four mechanistic treatment classes:

Nucleoside reverse transcriptase inhibitors (NRTI)

Non-nucleoside reverse transcriptase inhibitors (NNRTI)

Protease inhibitors, and

New class of drugs i.e. entry inhibitors.

Combination therapies often reduce patient viremia to an undetectable level and significantly delay disease progression in most treated individuals and show considerable morbidity and mortality. However, shortcomings, such as the emergence of drug-resistant HIV strains, pill burden, adverse side effects, and/or insufficient potencies, have resulted in 30 to 50% of therapeutic failures. With up to 20% of the new infections involving variants resistant to current medications, antiretroviral agents targeting new steps in the replicative cycle and lacking cross resistance to existing drug classes are needed for managing HIV infection. One highly promising approach to improve AIDS therapy is the inhibition of virus entry. The introduction of entry inhibitors provided a promising prospect for anti-HIV therapy because; viruses resistant to reverse transcriptase and protease inhibitors are sensitive to these compounds. There is an increasing need to develop effective inhibitors of HIV-1 entry into target cells for both application in therapy and prevention. The development of specific HIV inhibitors is considered particularly important in limiting the spread of HIV-1.

HIV-1 is a member of the Retroviridae family belonging to the genus lentiviruses. The Retroviridae are enveloped viruses containing two positive sense RNA strands that are converted into dsDNA by the highly error-prone viral reverse transcriptase enzyme. HIV-1 falls into three groups: M (Major/Main), N (Non-M, Non-O/New) and O (Outlier) of which, group M is most common. Group M is subdivided into several subtypes or clades (A-D, F-H, J and K), of which B is most common in the Western world, whilst C is the predominant subtype found primarily in India, China and sub-Saharan Africa. The remaining subtypes, as well as HIV-1 variants with characteristics of several different subtypes, so-called circulating recombinant forms (CRFs), are dispersed throughout Africa and other parts of the world.

The first step of the HIV replication is the entry of virus into the target cell. The entry of HIV into target cells is mediated by their envelope proteins. The HIV virion surface is coated with viral protein envelope (Env), Env is a homotrimeric type I integral membrane protein, each Env subunit consists of a three gp120 (glycoprotein 120) surface protein that mediates binding to cellular receptors and a noncovalently associated three gp41 transmembrane protein that has a hydrophobic fusion peptide at its N terminus. These proteins (gp120, gp41) are generated by cleavage of a heavily glycosylated precursor protein, gp160, by furin-like enzymes during transport through the Golgi apparatus.

The process of entry of HIV requires the sequential interaction of gp120 with two host surface proteins, CD4 and a chemokine receptor (CCR5 or CXCR4). CD4 is a transmembrane glycoprotein that is mainly expressed by T-lymphocytes, monocytes/macrophages and dendritic cells. The CD4 receptor normally functions as a coligand and coreceptor of the major histocompatibility complex class II (MHC II) molecule during T cell recognition of a foreign antigens. The interaction of gp120 with the chemokine receptor largely accounts for differences in HIV tropism among CD4-positive cells. In addition, chemokine receptor specificity contributes substantially to HIV pathogenesis. Viruses that use CCR5 are largely responsible for HIV transmission, and individuals lacking functional CCR5 due to a 32-bp deletion in the CCR5 gene (ccr5 Δ32 allele) are highly resistant to HIV especially to HIV-1 type infection. Chemokine receptors are members of the G-protein-coupled receptor (GPCR) superfamily that possess seven transmembrane (TM) domains. The N-terminus is extracellular and participates in binding of the chemokine; the C-terminus is intracellular and serves as the site for β-arrestin binding. β-arrestins facilitate G-protein independent cell signaling in addition to binding the chemokine receptor to clathrin for endocytosis and subsequent recycling.

The ligands for CCR5 and CXCR4 are chemokines, which are small molecules in the cytokine family that promote zhemotaxis and cellular activation; on binding to their receptor on the target cell, an intracellular signaling cascade is initiated via a G-protein release from the intracellular domain of the Receptor. Native ligands for CCR5 include chemokines MIP-1 (macrophage inflammatory protein) and RANTES (regulated on activation normal T cell expressed and secreted). CCR5 and CXCR4 are expressed on immune cells, including effector and memory T-cells, natural killer cells, and antigen presenting cells.

FIG.1 Structure of HIV glycoproteins and host cell receptors

The binding of gp120 to CD4 triggers a cascade of conformational changes in the viral envelope protein. CD4-gp120 binding causes extensive conformational changes in gp120 that involve movement of V1/V2 and V3 hypervariable loops and exposure and/or formation of a highly conserved domain in gp120 shown to be important for CCR5 binding. This domain consists of residues adjacent to and within a region termed the bridging sheet, which consists of a four-stranded, antiparallel β sheet formed by the V1/V2 stem of gp120. While the V3 loop has been shown to contribute to the specificity of CCR5 or CXCR4 utilization. V3 of the HIV-1 gp120 envelope glycoprotein is immunodominant and contains features essential for coreceptor binding. V3 acts as a molecular hook and determines which coreceptor, CXCR4 or CCR5, will be used for entry. This conformational change in gp120, which both increases its affinity for a coreceptor and exposes gp41 leads to the penetration the cell membrane by gp41, which approximates the membrane of HIV and the T cell and promotes their fusion, followed by the entry of the viral core into the cell. These processes seem to be mediated in part by the formation of a triple-stranded coiled coil from the N-terminal helical regions, termed HR1, of each of the three gp41 ectodomains (Fig. 1). Formation of this structure can be induced by CD4 binding alone. The gp41 subunit then folds back on itself, allowing a second, more C-terminal helical region, termed HR2, to pack into grooves on the outside of the triple-stranded coiled coil. Eventually, a six-helix bundle is formed, comprising three HR1 domains in the center, with three HR2 domains packed on the outside in an antiparallel fashion . As a result of this transition, the fusion peptide and transmembrane domain of gp41, along with their associated membranes, are brought into close proximity .The change in free energy associated with this structural transition is predicted to be sufficient to cause lipid mixing and membrane fusion.

FIG 1. Mechanism of binding and fusion of HIV

Thus, of the sequential events of HIV entry process (i.e.,virion attachment to CD4, coreceptor binding, and virion-cell membrane fusion), the binding of gp120 and CD4 molecules clearly dictates the subsequent key steps of viral invasion into the host cells. Despite this detailed knowledge of the membrane fusion pathway, the factors that control efficiencies and rates of entry are largely unknown. Moreover, numerous changes in gp120 and gp41 occur during disease progression, yet the effects of these changes on the steps of infection are also substantially unknown.

Entry inhibitors mark the beginning of a new era in the management of human immunodeficiency virus type 1 (HIV-1) disease. With a unique mechanism of action they represent a fourth class of antiretrovirals. All entry inhibitors target the viral Env protein directly or indirectly (e.g., coreceptor blockers)7. Entry inhibitors are a new class of anti-HIV drugs that work by blocking the virus ability to infect a cell. HIV entry inhibitors include coreceptor antagonists which are under clinical development and the fusion inhibitor. Entry inhibitors lock HIV outside the target cell and thereby should limit the ability of the virus to replenish its latent cellular reservoirs, which represent the primary hurdle on the way toward HIV eradication. Entry inhibitors are also receiving increasing attention as topical 'microbicides' for the prophylaxis of HIV transmission.

The drugs which block the entry of HIV into the target cells are classified into:

CD4 binding inhibitors

Coreceptor binding inhibitors

CCR5 binding inhibitors

CXCR4 binding inhibitors

3) Fusion inhibitors

FIG.2 Target areas for various Binding inhibitors

A model for HIV entry is shown, with the steps prevented by different entry inhibitors.

CD4 binding inhibitors: These are the class of drugs which blocks the attachment of HIV to the CD4-receptor

TNX-355: TNX-355 is the most-advanced antibody in development for the treatment of HIV/AIDS. TNX-355 (formerly hu5A8) is a humanized murine IgG4 monoclonal antibody that binds to a unique epitope in domain 2 of the CD4 molecule that is involved in the conformational change required for entry into target cells following binding of the virus to the CD4 molecule. TNX-355 was fast tracked by the Food and Drug Administration in 2003. The fast-track designation is designed to expedite approval of therapies for life-threatening diseases and allows for rolling new drug application (NDA) submissions. As the TNX-355 epitope lies outside the D1-located binding site of class II molecules on CD4, it apparently does not interfere with the normal immunological functions of CD4. A single dose of TNX-355 reduced viral load and increased CD4+ T-cell counts in HIV-1-infected patients and phase II clinical trial results showed a more than 2 log reduction in viral load after 24 weeks of treatment. TNX-355 may have an adjunct role in salvage therapy in the near future, if the clinical data continues to be positive.

PRO 542: Use of Ig-based fusion proteins is acquiring an important place in medicine. Because of the IgG Fc region of these proteins, there is a possibility that interactions with Fc receptors may interfere with dose-dependent therapeutics.PRO 542 is a novel inhibitor of HIV-1 attachment and entry. PRO 542 is a tetravalent CD4-immunoglobulin fusion protein that comprises the D1 and D2 domains of human CD4 genetically fused to the heavy and light chain constant regions of human IgG2. CD4-g2 is a homodimer comprising D1D2 genetically fused to the hinge and Fc region of the g2 heavy chain. Unlike monovalent and divalent CD4-based proteins, CD4-IgG2 broadly and potently neutralizes primary human immunodeficiency virus type 1 (HIV-1) isolates and has demonstrated encouraging antiviral activity in humans. Compared to prior-generation CD4-based proteins, PRO 542 possesses greater valency, size, and conformational flexibility, and these structural features may contribute to its enhanced antiviral activity. PRO 542 has demonstrated antiviral activity without appreciable toxicity clinical trials in HIV-infected adults and children. In addition, PRO 542 was well tolerated. Thus, PRO 542 may hold promise for salvage therapy of HIV-1 infection.

BMS 806: BMS-378806 (herein called BMS-806) and related compounds are low-molecular-weight inhibitors of HIV-1 entry. BMS-806 and the related compounds are novel inhibitors of human immunodeficiency virus type 1 (HIV-1) entry that binds the gp120 exterior envelope glycoprotein. BMS-806 and related compounds block conformational changes in the HIV-1 envelope glycoproteins that are induced by binding to the host cell receptor. CD4 BMS-806 was shown to be specific for HIV-1, with no activity against HIV-2 or simian immunodeficiency virus. BMS-806 is active against HIV-1 isolates irrespective of chemokine receptor preference. BMS-806 binds gp120, and changes in particular gp120 amino acid residues can alter the sensitivity of the virus to BMS-806. The ability of small, potent inhibitors of HIV-1 entry to block the CD4-induced creation and/or exposure of the gp41 HR1 coiled coil supports the importance of this event for envelope glycoprotein function.

Coreceptor binding inhibitors:

Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors CCR5 is an emerging strategy for antiretroviral therapy. Currently, several novel coreceptor inhibitors are being developed in the clinic, and early results have proven promising. CCR5 antagonists are the small-molecule inhibitors. These are cheaper to produce than peptides with better oral bioavailability, these agents also possess significant potency across diverse clades with half maximal inhibitory concentrations (IC50) measured in nanomoles. As is the case with many small-molecule inhibitors of G-coupled proteins, these agents appear to bind a pocket within the transmembrane helices, alter extracellular CCR5 conformation, and thereby inhibit HIV-1 binding. Agents that have progressed from simple labels to scientific names end in the suffix-viroc, eg, vicriviroc, to denote their action of viral receptor occupancy. Maraviroc recently got approval for their use.

SCH-C (SCH 351125) is a small-molecule oxime-piperidine antagonist of the HIV-1 coreceptor CCR5. It has potent activity against clinical HIV-1 R5 isolates, both in vitro and in vivo. SCH-C has good oral bioavailability (50 to 60%) in rodents and primates, with a serum half-life of 5 to 6 h. It is now being studied in phase I clinical trials.

Vicriviroc/SCH-D/SCH 417690: Vicriviroc is a potent inhibitor of HIV-1 infection that acts by specifically blocking the viral coreceptor CCR5. Clinical findings reported that vicriviroc possess broad-spectrum antiviral activity. This, in conjunction with favorable pharmacokinetic properties, supports the further development of vicriviroc as a novel antiviral agent for the treatment of HIV-1 infection.

PRO 140: It is humanized monoclonal antibody, considered a fast-track product by the FDA, reported positive proof-of-concept study results. A phase I study in 39 HIV-positive patients with CCR5-tropic virus demonstrated PRO 140 to be safe, well tolerated and a potent inhibitor of HIV-1 replication. PRO140 binds to the N terminus and second extracellular domain of CCR5 and acts as a direct competitive inhibitor of HIV binding.

Maraviroc: Maraviroc originally designated UK-427857, was developed by the drug company Pfizer. The oral pill was cleared by the US Food and Drug Administration (FDA) for patients who have failed to reduce the levels of the human immunodeficiency virus (HIV) with other treatments. Maraviroc, an anti retroviral drug is approved for use in combination with other antiretroviral drugs for the treatment of adults infected with CCR5 tropic HIV-1. It can be used in conditions where resistance to other available antiretroviral drugs is encountered. Maraviroc blocks the chemokine co receptor CCR5 and inhibits the interaction between the viral gp 120 and host CCR5 co receptor. Thus the viral entry into the cell is inhibited. The other co-receptor used by HIV-1 CXCR4, is however unaffected. Resistance to other groups of drug namely NRTIs, NNRTIs, and protease inhibitors do not produce cross resistance to maraviroc. Maraviroc is not recommended for monotherapy or for patients in whom antiretroviral therapy is being started for the first time. When patients with HIV-1 are treated with maraviroc, the X4 tropic viruses seem to emerge. Identification of the viral tropism is essential for treatment with maraviroc. In adults it has no apparent significant adverse effects. The drug has not been tested in children less than sixteen years and in pregnant women. The effectiveness of maraviroc as a monotherapy for HIV 1 infection and for patients not treated with any other antiretroviral therapy has not been established.

FIG.4 Mechanism of antibody to block entry of HIV-I

Fusion inhibitors: Enfuvirtide is the first of a novel class of antiretrovirals called fusion inhibitors to receive approval for clinical use. Enfuvirtide (ENF) is a synthetic 36-amino-acid oligopeptide that inhibits fusion of HIV-1 to CD4-cells by binding to the first heptad repeat (HR-1) of gp41, the transmembrane subunit of the viral envelope glycoprotein.

The mechanism by which ENF operates is unique as it targets a structural intermediate of the fusion process. Its binding site in the HR1 region of gp41 becomes available only after Env binds to CD4. Multiple coreceptor binding events then enable several Env trimers to undergo the final conformational changes that lead to fusion, with six-helix bundle formation occurring rapidly after a full repertoire of coreceptors are engaged. Membrane fusion occurs coincident with six-helix bundle formation or shortly thereafter. Thus, T-20 target Env only during a kinetic window that appears to be opened by CD4 binding and closed by coreceptor engagement.

FIG.3 Mechanism of T-20

ENF was approved in 2003 as a salvage therapy agent, ENF is only FDA approved for patients who have failed treatment with other agents, and thus is not recommended for initial therapy. ENF is a novel therapeutic agent, and represents a valuable choice for treatment experienced patients who otherwise have few options for effective treatment. Unlike PI and NNRTI, enfuvirtide (ENF) is administered by subcutaneous injection. It is not metabolized via the cytochrome system. Because of these characteristics, drug exposure is assumed to be less variable and drug-drug interactions are thought to be less important with ENF than with PI or NNRTI. Resistance to enfuvirtide is mediated by substitutions within HR-1 at amino acids 36 to 45 of gp41. The mutations confer significantly reduced binding of enfuvirtide to HR-1 and a substantial decrease in antiviral activity in vitro.

ENF-resistance has not been shown to confer cross resistance to other inhibitors including fusion inhibitors, coreceptor inhibitors, and agents that target CD4 binding. ENF has been successfully used to produce durable reductions in viremia even in patients with multi-drug resistance. ENF should be administered in conjunction with an optimized background HIV regimen. Resistance testing is recommended in patients receiving enfuvirtide in order to select an appropriate therapeutic background regimen. The best possible initiation time for ENF treatment is when the patient can be predicted to have a strong, sustained virologic response.

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