Drug Resistance of Human Immunodeficiency Virus and Overcoming It by Natural Products
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in vivo 23: 1-6 (2009) Review Drug Resistance of Human Immunodeficiency Virus and Overcoming it by Natural Products JULIA HUPFELD1 and THOMAS EFFERTH2 1University of Heidelberg, Institute of Pharmacy and Molecular Biotechnology, Heidelberg; 2German Cancer Research Center, Pharmaceutical Biology (C015), Heidelberg, Germany Abstract. Acquired immune deficiency syndrome (AIDS) HIV and Standard Anti-HIV Therapy caused by infection with the human immunodeficiency virus (HIV) represents a major health problem worldwide, especially HIV is a lentivirus belonging to the Retroviridae family. in developing countries. Combinational anti-HIV therapy has Its genome contains three major genes: gag, pol and env. largely improved patients’ lives, but is not widely available in The gag gene encodes for a Gag precursor protein, which developing countries. Moreover, drug resistance is a main is cleaved by the viral protease into matrix, capsid and problem during HIV treatment. Therefore, there is a continuous nucleocapsid proteins. The pol gene encodes viral need for new drugs effective against otherwise drug-resistant enzymes, which are initially synthesized as GagPol HIV strains. Chemical compounds from natural sources provide precursor proteins. The precursor proteins are cleaved by a large variety of potential anti-HIV compounds. The most the viral protease resulting in formation of the viral promising natural products are discussed in this review. enzymes polymerase, integrase and protease. The envelope glycoprotein (Env) is also first expressed as a precursor Even though the number of new human immunodeficiency polyprotein, which is then cleaved by cellular proteases virus (HIV) infections is decreasing, acquired immune into the surface protein gp120 and the transmembrane deficiency syndrome (AIDS) is still one of the leading causes protein gp41 (3). of deaths worldwide. In 2007, an estimated 33.2 million people HIV infects CD4+ T-lymphocytes, resulting in their globally were infected with AIDS. The virus represents a major depletion and in subsequent immunodeficiency. The CD4 threat in developing countries, where over 95% of all infected molecule was the first and principal retroviral receptor people worldwide are living (1). In Africa, AIDS remains the identified (4). Binding of the virus to the CD4 receptor via main cause of death. Sub-Saharan Africa is most rigorously gp120 represents the initial step of host cell infection. affected, with over two-thirds of the population infected with However, for membrane fusion and virus entry, additional HIV. Even though there is still no cure for AIDS, advances in binding of gp120 to a co-receptor is necessary. M-tropic HIV treatment have improved patients’ quality of life and viruses generally use the CCR5 chemokine co-receptor prolonged their lives (2). However, the high cost of treatment (“R5” virus), while T-tropic viruses usually bind to the is a major problem in developing countries. Additionally, there chemokine CXCR4 receptor (“X4” virus). Receptor are several limitations to standard HIV therapy such as drug binding induces a conformational change of the gp120 resistance and dose-limiting side-effects. Therefore, medicinal protein and subsequently a change in the gp41 protein, the plants and their chemical constituents with activity against HIV latter being responsible for fusion of the virus with the host have come into the focus of virus research. cell membrane (5). Following membrane fusion, the viral core is released into the host cytoplasm. The virus mRNA is then reverse transcribed into cDNA by the viral enzyme reverse transcriptase (RT). This enzyme also synthesizes Correspondence to: Professor Dr. Thomas Efferth, German Cancer the complementary DNA strand and exerts RNAse activity. Research Center, Pharmaceutical Biology (C015), Im Neuenheimer The double-stranded DNA is translocated into the nucleus, Feld 280, 69120 Heidelberg, Germany. Tel: +49 6221 423426, Fax: where its integration into the host genome is catalyzed by +49 6221 423433, e-mail: [email protected] the viral enzyme integrase (IN) (6). Inside the host Key Words: Antiviral agents, chemotherapy, drug resistance, human genome, the so-called provirus can remain latent for a long immunodeficiency virus, natural products, pharmacognosy, review. period of time. Once transcribed, both spliced and 0258-851X/2009 $2.00+.40 1 in vivo 23: 1-6 (2009) unspliced RNAs are generated and transported into the cell Table I. Anti-HIV drugs currently approved by the Food and Drug cytoplasm. After synthesis of viral proteins, virus particles Administration (FDA) of the U.S.A. Anti-HIV drugs can be grouped into assemble at the host cell membrane. This process is mainly four different inhibitor classes. The largest classes are reverse transcriptase inhibitors and protease inhibitors, while only two entry regulated by the Gag precursor proteins. Eventually, the inhibitors and one integrase inhibitor are currently FDA-approved. virus particle is released by budding of the cell (7). In order to be infectious, additional maturation of the virus is Reverse transcriptase Protease Entry Integrase necessary. During this process, which takes place during or shortly after release of the virus (3), the Gag and GagPol NRTI NNRTI Abacavir Delavirdine Amprenavir Enfuvirtide Raltegravir precursor proteins are cleaved into the mature Gag and Pol Didanosine Efavirenz Atazanavir Maraviroc proteins by the viral protease. Emtricitabine Etravirine Darunavir Anti-HIV drugs target the different steps of the virus life Lamivudine Nevirapine Fosamprenavir cycle. Currently 24 drugs for HIV treatment are approved by Stavudine Indinavir the Food and Drug Administration (FDA) of the U.S.A. They Tenofovir Lopinavir Zidovudine Nelvinavir can be classified into four different groups: fusion or entry Ritonavir* inhibitors (FI), reverse transcriptase inhibitors, integrase Saquinavir1 inhibitors (IN), and protease inhibitors (PI) (Table I). Current Tipranavir anti-HIV protocols are fairly individualized, based on the patient’s medical history, CD4+ T-cell count, viral load and NRTI: Nucleoside analogue reverse transcriptase inhibitors; NNRTI: non-nucleoside reverse transcriptase inhibitors. *Used in combination resistance assays (8). During standard HIV therapy, which is with other protease inhibitors to boost their effect; 1no longer marketed. also referred to as HAART (highly active antiretroviral therapy), a combination of three or more drugs is administered. This combinational therapy reduces the emergence of resistant virus particles, which represents a is one of the main reasons for therapy failure (14). As drug major problem in anti-HIV therapy. resistance is a major problem in anti-HIV therapy, The group of nucleoside analogue reverse transcriptase mutations leading to resistance have been widely (RT) inhibitors (NRTIs) is composed of various nucleoside investigated and mutation profiles for the currently analogs. Inside the host cell, these prodrugs need to be approved drugs have been developed. For a comprehensive metabolically activated by phosphorylation. They inhibit review of mutation profiles, the reader is referred to the activity of RT by termination of chain elongation. Non- Johnson et al. (15). Moreover, cross resistance to drugs of nucleoside reverse transcriptase inhibitors (NNRTIs) do the same class is a major problem, as illustrated by not need metabolic activation. They inhibit RT in a non- thymidine analogue-associated mutations (TAMs). TAMs competitive manner by binding to the enzyme. Most PIs are selected by thymidine anaolgues such as zidovudine are administered in combination with ritonavir, which and stavudine and lead to cross-resistance to all currently boosts the effect of other PIs by inhibiting the cytochrome approved NRTIs (16, 17). In NNRTI-associated mutations, P450 (CYP) 3A4 isoenzyme (8). As CYP 3A4 metabolizes cross-resistance to drugs of the same class frequently PIs, co-administration of ritonavir allows reduced dosing emerges by the simple occurrence of only one mutation at of these PIs. codon 103 or 166, respectively. The FIs either prevent formation of the entry pore by Three or more mutations are often required for PI- binding to gp41 (enfuvirtide) (9) or block the CCR5 co- associated resistance depending on the drug used. Resistance receptor (maraviroc) (10). The latter drug is only active to FIs is caused mainly by mutations in the env gene. against R5 viruses as X4 viruses bind to the CXCR4 co- Depending on the drug target, these mutations are primarily receptor. The first IN inhibitor, raltegravir, was only recently but not exclusively found in the gp41 gene (enfuvirtide) or approved by the FDA in October 2007 (11). the gp120 gene (maraviroc). Mutations in genes of two pathways have been identified Drug Resistance as mediating resistance towards the IN inhibitor, raltegravir. Gene mutations of each pathway comprise at least one Drug-resistant mutations arise and accumulate frequently mutation in the integrase gene. in the HIV genome. This is mainly due to two reasons: (a) Considering the significant problem of drug resistance the lack of proof-reading activity of the RT, resulting in a during anti-HIV therapy, there is a continuing interest in high mutation rate during virus replication (about 3.4×10–5 finding new agents which are not only well tolerated, mutations per bp per replication cycle) (12) and (b) the convenient and less expensive, but which are also active high replication rate of HIV (13). All current anti-HIV