Virus, human immunodeficiency

In 1997, it was estimated that 30 million adults were infected with the human immunodeficiency virus (HIV) worldwide, with increments of five people infected every minute. It is estimated that approximately 7% of the population of sub-Saharan Africa has been infected. The incubation of the disease is 7 to 8 years. Currently available drugs for acquired immunodeficiency syndrome (AIDS) and HIV are zidovudine, didanosine, lamivudine, and stavudine. The causative agent for AIDS is generally an HIV virus, which is transmitted by sexual contact, blood and blood products, the use of contaminated drug needles, and from mother to fetus. 

AIDS is now a pandemic, and according to the Joint United Nations Program on HIV/AIDS, 58 million people have been infected with HIV and 25 million have died worldwide. In the twenty-first century, it remains an ultimately fatal disease that is difficult to treat, but the development of new drugs has improved the outlook of patients infected with the virus in the United States and Western Europe. 

As noted in Volume 6, the development of these agents was greatly facilitated by a discovery in a seemingly unrelated area. Research aimed 

This moiety may be viewed as a carbon analogue of the transition state in peptide cleavage. The fragment is apparently close enough in structure to such an intermediate as to fit the cleavage site in peptidase enzymes. Once bound, this inactivates the enzyme as it lacks the scissile carbon-nitrogen bond. All five newer HIV protease inhibitors incorporate this structural unit. 

One scheme for preparing a key intermediate for incorporating that fragment begins with the chloromethyl ketone (1) derived from phenylalanine, in which the amine is protected as a carbobenzyloxy (Cbz) group. Reduction of the carbonyl group by means of borohydride affords a mixture of aminoalcohols. The major syn isomer 2 is then isolated. Treatment of 2 with base leads to internal displacement of halogen and formation of the epoxide (3).  

Much the same sequence leads to a protease inhibitor that incorporates a somewhat more complex fiiryl function-linked oxygen heterocychc. This fused bis(tetrahydrofuryl) alcohol (16) was designed to better interact with a pocket on the viral protease. The first step in preparing this intermediate consists of reaction of dihydrofuran (13) with propargyl alcohol and iodosuccinimide to afford the iodoether (14). Free radical displacement of the iodine catalyzed by cobaloxime leads to the fused 

That product (17) is then converted to the activated A -hydoxysuccinimide derivative 18 as in the case of the monocyclic furan. Reaction with the primary amine 10 used to prepare amprenavir then leads to the urethane (19). Reduction of the nitro group then affords darunavir (20). 

HIV affects the immune system, rendering the infected individual vulnerable to a wide range of disorders. Infections typically lead to the death of the patient. Symptoms can occur within a month and can include fever, diarrhea, fatigue, and rash. Exposed persons may develop antibodies and not present symptoms for months to years. The infected person may finally develop a wide range of symptoms depending on the opportunistic infections against which the body s immune system cannot defend (Tables 8.6 through 8.8). 

Contact with blood, semen, vaginal secretions, and breast milk Sexual intercourse 

Contact with HIV-infected blood under the skin, mucous manbranes, or broken skin Mother-to-child contact at the time of birth Blood transfusions or organ transplants 

Saliva and blood contacted during dental procedures 

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The viruses responsible for AIDS are human immunodeficiency virus 1 and 2 (HIV 1 and HIV 2) Both are retroviruses, meaning that their genetic material is RNA rather than DNA HI Vs require a host cell to reproduce and the hosts m humans are the T4 lymphocytes which are the cells primarily responsible for inducing the immune system to respond when provoked The HIV penetrates the cell wall of a T4 lymphocyte and deposits both its RNA and an enzyme called reverse transcriptase inside There the reverse transcriptase catalyzes the formation of a DNA strand that is complementary to the viral RNA The transcribed DNA then serves as the template from which the host lymphocyte produces copies of the virus which then leave the host to infect other T4 cells In the course of HIV reproduction the ability of the T4 lymphocyte to reproduce Itself IS compromised As the number of T4 cells decrease so does the body s ability to combat infections... 

Human Immunodeficiency Virus. Human immunodeficiency vims (HIV) causes Acquired Immunodeficiency Syndrome (AIDS), which has no cure. HIV infects the cells of the human immune system, such as T-lymphocytes, monocytes, and macrophages. After a long period of latency and persistent infection, it results in the progressive decline of the immune system, and leads to full-blown AIDS, resulting in death. 

Rossmann, M.G. Antiviral agents targeted to interact with viral capsid proteins and a possible application to human immunodeficiency virus. Proc. Natl. Acad. Sci. USA, 85 4625-4627, 1988. 

Human immunodeficiency virus type 1 (infection with) (Vol. 67 1996)... 

In patients infected with HIV (human immunodeficiency virus), the helper cell population is weakened to the point where the immune system is no longer able to function properly. The body thus becomes susceptible to otherwise nonlethal diseases such as pneumonia. 

M. A., Dorns, R. W., and Peiper, S. C. (1997). Two distinct CCR5 domains can mediate coreceptor usage by human immunodeficiency virus type 1. J. Virol. 71 6305-6314. 

Smyth, R. J., Yi, Y., Singh, A., and Collman, R. G. (1998). Determinants of entry cofactor utilization and tropism in a dualtropic human immunodeficiency virus type 1 isolate. J. Virol. 72 4478-4484. 

Ullum, H., Lepri, A. C., Victor, J., Aladdin, H., Phillips, A. N., Gerstoft, J., Skinhoj, P., and Pedersen, B. K. (1998). Production of beta-chemokines in human immunodeficiency virus (HIV) infection Evidence that high levels of macrophage in inflammatory protein-1-beta are asociated with a decreased risk of HIV progression. J. Infect. Dis. 177 331-336. 

Luciw P (1996) Human immunodeficiency viruses and their replication. In Fields BN, Knipe DN, Howley, PM (eds) Virology. Lippincott-Raven publishers, Philadelphia, PA, pp 1881-1952... 

Human immunodeficiency virus (HIV) (combined with other drugs)... 

The term generic indicates the drug is available in generic form. Gl, gastrointestinal HIV, human immunodeficiency virus. 

AIDS After considerable research, the causative agent for AIDS was identified as a virus, which was eventually named the Human Immunodeficiency Virus (HIV). 

Cooper OB, Brown TT, Dobs AS Opiate drug use a potential contributor to the endocrine and metabolic complications in human immunodeficiency virus disease. Clin Infect Dis 37(suppl 2) S132—S136, 2003... 

Luban J (2007) Cyclophihn A, TRIM5, and resistance to human immunodeficiency virus type 1 infection. J Virol 81 1054-1061... 

Mansky LM, Temin HM (1995) Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase, J Virol 69 5087-5094... 

Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, Lifson JD, BonhoefferS, Nowak MA, Hahn BH et al. (1995) Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373 117-122... 

CarriUo A, Stewart KD, Sham HL, Norbeck DW, Kohlbrenner WE, Leonard JM, Kempf DJ, Molla A (1998) In vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor. J Virol 72 7532-7541 Chambers TJ, Nestorowicz A, Amberg SM, Rice CM (1993) Mutagenesis of the yellow fever virus NS2B protein effects on proteolytic processing, NS2B-NS3 complex formation, and viral replication. J Virol 67 6797-6807... 

Craig JC, Duncan IB, Hockley D, Grief C, Roberts NA, Mills JS (1991) Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase. Antiviral Res 16 295-305... 

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