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Genetic Basis

Prevalence

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HIV CME

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Facts & Figures






HIV and other retroviruses carry their genetic information on RNA molecules. Once the RNA virus has infected a cell, the genetic information encoded on the viral RNA is converted, or "transcribed," into genetic information on a DNA molecule. The process of transcribing viral RNA to DNA is called "reverse transcription" and is under the control of the reverse transcriptase enzyme. This new DNA strand is a mirror image of the viral RNA gene sequence, and becomes incorporated into the genetic makeup of the infected cell. Once inserted into the infected cell DNA, these viral genes can be expressed by the host cell, leading to production of new viral particles. For HIV, the process of reverse transcription is complicated by a high natural error rate, which leads to a high rate of spontaneous gene mutations. These mutated viral strains are stored in the lymphoid tissue and may emerge when antiretroviral therapy gives them a selective advantage. HIV has 3 main structural genes: gag, pol, and env. The gag gene codes for nucleocapsid proteins; pol codes for enzymes such as reverse transcriptase, protease, and integrase; and the env gene codes for surface proteins. Mutations within these genes account for the development of drug resistance in HIV-infected patients.

Mutations affecting the reverse transcriptase enzyme may lead to resistance to nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors. Mutations affecting the protease enzyme lead to resistance to protease inhibitors, while mutations affecting surface proteins lead to resistance to fusion inhibitors. Resistance to some drugs can occur after just 1 mutation, while others require multiple mutations before resistance is established.

In the early days of HIV, most new patients were infected with viral strains with few or no resistance mutations. Following decades of antiretroviral therapy, however, the prevalence of drug-resistant strains has increased to the point that new HIV patients may already be infected with a multidrug-resistant strain. The presence of so many mutations that already exist prior to therapeutic initiation explains why maximal suppression of replication is key to sustained virologic response in the treatment of patients with HIV. It also explains the rationale for early treatment of patients with acute HIV infection, as prompt treatment may decrease the number of resistant strains formed during the initial stages of infection.

The inevitable development of resistance has led to the principle of treating HIV with multiple agents that attack the virus at different places, known as highly-active antiretroviral therapy (HAART). Because HIV may continue to mutate during treatment with HAART, the regimen often changes over time to address the changing resistance pattern. Understanding the genetics of resistance aids in the design of new drugs and in crafting new drug combinations for the treatment of HIV.



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