Use of chimeric human immunodeficiency virus types 1 and 2 reverse transcriptases for structure-function analysis and for mapping susceptibility to nonnucleoside inhibitors

Article Abstract:

A specific part of HIV-2 reverse transcriptase (RT) appears to confer resistance to a nonnucleoside RT inhibitor. RT is an HIV enzyme that is required for the reproduction of HIV. Researchers spliced pieces of the HIV-1 RT and the HIV-2 RT together to examine the structural basis of the enzyme's function and to determine which pieces of HIV-2 RT are responsible for the resistance of HIV-2 to the nonnucleoside RT inhibitor TIBO R82150. Two regions of RT, called the finger and palm subdomains, had to be moved as a single piece during the splicing process in order for the enzyme's activity to remain normal. This suggested that there were interactions between these regions that were crucial to the proper functioning of the enzyme. A certain piece of HIV-2 RT, when used to replace a similar piece in HIV-1 RT, was responsible for a 40-fold increase in the resistance of HIV-1 RT to TIBO R82150. A single amino acid within this piece was shown to have a key role in the drug resistance, but could not by itself confer resistance.

Analysis, Structure-activity relationships (Biochemistry), Reverse transcriptase

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Individualization of therapy using viral markers

Article Abstract:

Individual drug therapy for HIV-infected people may consist of a series of regimens with special emphasis on changing viral markers. Although it is widely accepted that triple drug combinations are better than dual drug combinations and that all protocols should contain zidovudine (AZT), overlapping toxicities and cross-resistance pose additional challenges. Individual patient responses to any drug regimen differ widely, requiring detailed analysis of AZT-resistance and viral load levels. Analytic technology measuring viral load requires FDA approval to ensure widespread use in clinics. Depending on CD4 count reductions and viral load increases, alternative drug regimens would be introduced in patients constantly monitored with respect to these physiological changes. As a result of attending to such changes immediately, immune function may be preserved.

Health aspects

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Therapeutic interventions in primary HIV infection

Article Abstract:

Treatment of primary HIV infection (PHI) should consist of very early drug intervention with the goal of promoting long-term disease stability. Newly infected patients benefit from early drug therapy because of its higher effectiveness, lower toxicity, and better tolerance in the early disease stages. Virus load seems to remain high in the lymphoid tissues even in the initial absence of viremia, suggesting disease activity. Capitalizing on a fairly intact immune system, antiviral therapy immediately after HIV diagnosis can achieve maximum results before immunity disintegrates. Drugs of choice include zidovudine, 3TC, and a protease inhibitor, such as MK-639 or ABT-538. The initial treatment period should be for about one year with special attention focused on patient compliance and the management of toxic side effects.

Evaluation, Drug therapy, Combination, Combination drug therapy

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