Directions of HIV Drug Development: Part I

Callie Deng

Johns Hopkins University

Publication Date: May 11, 2015

Since its discovery in the early 1980s, HIV has become one of the best-studied pathogens in biomedical research. To date, there is no reliable cure; current treatments consist of various anti-retroviral therapies used in combination to mitigate and control viral load. But the shift from what was formerly an undiagnosed and lethal disease to a chronic yet treatable condition reflects the progress translational research has had on extending the length and quality of life of HIV patients. Recently, the global AIDS community announced its ambitious “90-90-90” treatment target: by 2020, 90% of all people living with HIV should know their HIV status, 90% of those who test positive for HIV should be provided therapy, and of those, 90% should achieve virologic suppression.1

In 1983 the retrovirus known as HIV-1 was independently isolated from AIDS patients, in two separate research labs headed by Robert Gallo and Luc Montagnier 2,3. At the time, the disease was largely mislabeled as an immune deficiency confined to the male homosexual population; however, subsequent contractions revealed that this was not the case. Following the discovery of HIV-1, researchers isolated glycoprotein CD4, a cell surface molecule found on helper T-cells that functions as the main binding receptor of HIV. In this way, HIV disables the population of cells critical to the body’s adaptive immune response. By the mid-1990s, researchers successfully isolated key co-receptors chemokines CXCR4 and CCR5. Binding of these chemokines results in a conformational change, conferring X4-torpic HIV-1 and R5-tropic HIV-1 entry, respectively. Researchers further identified individuals with a rare homozygous CCR5 deletion that made them resistant to HIV-1 infection by blocking viral entry.4

Current antiretroviral drugs target distinct phases of the viral life cycle. Effective treatment usual requires the combination of two or more antiretroviral drugs that target multiple phases of the HIV replication cycle. The main types of antiretroviral drugs include 1) entry/fusion inhibitors, 2) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), 3) non-nucleoside reverse transcriptase inhibitors (NNRTIs), 4) protease inhibitors, and 5) integrase inhibitors5. As the name suggests, entry/fusion inhibitors serve to prevent retroviral infection of cells by blocking their mechanisms of entry. For instance, chemokine receptor antagonists of this category block viral attachment and subsequent fusion into healthy cells. The remaining four antiretroviral drug types specifically target viral enzymes critical for HIV replication. NRTIs and NNRTIs target HIV’s genetic replication process of converting viral RNA into DNA by blocking reverse transcriptase. NRTIs are analogs of deoxynucleotides and act as competitive inhibitors for the active site in reverse transcriptase. Unlike normal deoxynucleotides, NRTIs lack the hydroxyl group necessary for DNA synthesis; incorporation of an NRTI in the growing viral DNA causes chain termination. NNRTIs, or non-nucleoside reverse transcriptase inhibitors act on a different binding site to directly block the function of reverse transcriptase.6

Following successful reverse transcription, the newly synthesized genetic material is transported to the nucleus of the healthy cell and integrated into the host genome via the enzyme integrase. Integrase inhibitors are of particular importance because they block infection before the viral DNA is integrated, the critical step of HIV reproduction. If, however, the retroviral DNA has been incorporated, normal transcription and translation takes place, producing viral polyproteins that reassemble to form HIV virions. In this step, protease is necessary to cleave viral polyproteins at specific locations to produce mature and infectious HIV virions.7 Thus, protease inhibitors target and disable the enzyme’s function, resulting in defective HIV replicates.

Antiretroviral treatments seek to effectively reduce the virus load, thereby mitigating the deleterious effects on the hosts’ immune system and making the virus less transmissible. This is helpful in preventing new infections, especially among the population of uninfected individuals with HIV-positive partners. However, one of the main obstacles to achieving this is HIV drug resistance. Following primary infection, the virus may acquire random mutations that confer drug tolerance. Once the virus reaches a threshold population size and heterogeneity, it is able to sustain such populations of drug-resistant clones against treatments that target only one phase of the viral replication cycle. The emergence and proliferation of these drug-resistant populations can overcome even the most highly effective treatments, particularly when they accrue multiple mutations for drug-resistance. 5

References

1) (2014). 90–90–90 – An ambitious treatment target to help … – UNAids. Retrieved February 15, 2015, from http://www.unaids.org/en/resources/documents/2014/90-90-90.

Gallo, R. C., Sarin, P. S., Gelmann, E. P., Robert-Guroff, M., Richardson, E., Kalyanaraman, V. S., Mann, D., Sidhu, G. D., Stahl, R. E., Zolla-Pazner, S., Leibowitch, J., and Popovic, M. (1983) Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science 220, 865– 867

[3] Barre ́-Sinoussi, F., Chermann, J. C., Rey, F., Nugeyre, M. T., Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C., Ve ́zinet-Brun, F., Rouzioux, C., Rozenbaum, W., and Montagnier, L. (1983) Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220, 868 – 871

[4] Barré-Sinoussi, F. (2013). Past, present and future: 30 years of HIV research : Nature … Retrieved from http://www.nature.com/nrmicro/journal/v11/n12/abs/nrmicro3132.html.

[5] Bock, C. (2012). Managing drug resistance in cancer: lessons from … – Nature. Retrieved from http://www.nature.com/articles/nrc3297.

[6] Arts, E. (2012). HIV-1 Antiretroviral Drug Therapy. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312400/.

[7] Kohl, N. (1988). Active human immunodeficiency virus protease is required … Retrieved from http://www.pnas.org/content/85/13/4686.

Image taken by Seth Pincus, Elizabeth Fischer and Austin Athman / National Institutes of Health

 

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