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Oppurtunities for Drug Discovery

Although the major viral targets — envelope, reverse transcriptase, integrase and protease — are already marked by drugs approved or nearing approval, there are a limitless number of new inhibitory mechanisms available for each of these viral proteins. For example, the maturation inhibitor bevirimat (also known as PA-457), which has shown anti-HIV activity in 10-day clinical trials, inhibits proteolysis by binding directly to a specific cleavage site in the gag polyprotein, rather than by binding to protease. Novel mechanisms can therefore be exploited for existing targets.

Replication cycle of HIV with current and possible targets for antiviral intervention.

 

As shown in Fig, there are many steps for potential pharmacological intervention in the replication cycle of HIV.

 

Despite this, approved drugs attack only three targets: reverse transcriptase; protease; and viral entry. 

 

Proteins that are targets for approved drugs are coloured green: gp160, reverse transcriptase, HIV protease and chemokine (C-C motif) receptor 5 (CCR5). Integrase (yellow) is a target in advanced clinical development.

 

Proteins that are more speculative drug targets are coloured red: chemokine (C-X-C motif ) receptor 4 (CXCR4), RNase H, tat, rev, nef and vif.

 

New NIH Fundings

The NIH recently granted $7.5 million to researchers from the Perelman School of Medicine and the Penn Center for AIDS Research for the development of a novel HIV-gene therapy.

 

Researchers will combine the viral entry inhibitor, C34, with the HIV coreceptor, CXCR4.

 

The fused synthetic molecule has the potential to block the HIV virus from entering CD4 T-cells, which would control the spread of HIV-1 without antiretroviral drug therapies

Human Immunodeficiency Virus (HIV); Right: VRC01 antibody (blue and green) binding to HIV (grey and red). The VRC01-HIV binding (red) takes place where the virus attaches to primary immune cells.

 

 

HIV-Neutralizing Antibodies

The next generation of pre-exposure prophylaxis (PrEP), and even HIV treatment may consist of antibodies that could be given as an intravenous infusion or an injection into the muscle, two presenters at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston have said.

 

The study found that this antibody—known as a broadly neutralizing antibody (bNAb) for its ability to defend against a wide range of HIV strains—is well tolerated and remained in the participants’ bloodstreams for weeks.

 

 Editing Human T Cells

 CXCR4, a co-receptor for HIV, was ablated in human T cells using the CRISPR/Cas9 system.

 

 

Recently, UCSF scientists have developed a new strategy to precisely modify human T cells using the CRISPR/Cas9 system.

 

Using their new strategy, the authors reported a higher frequency of targeted genome modifications in primary T cells. They ablated CXCR4, a co-receptor for HIV.

 

Approximately 40% of cells lost high-level expression of CXCR4, and sorting based on low CXCR4 expression could enrich for successfully edited cells.

 

In addition, they also successfully deactivated PD-1, a validated target for tumor immunotherapy.

 

Their findings suggest that this new technology could potentially contribute to the therapeutic correction of disease-associated mutations.

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