In the aftermath of World AIDS day on 1st December 2015, whereby the National AIDS Trust (NAT) encouraged the public to rethink outdated stereotypes and challenge myths by adopting the ‘Be positive: Rethink HIV’ campaign, it seems opportune to ‘rethink’ or reflect on the current landscape of medical research in this area – is it really something to ‘be positive’ about?
A devastating pandemic that has killed in excess of 35 million people since its identification in 1984 [1], the human immunodeficiency virus (HIV) still affects more than 100,000 people living in the UK, and 34 million people worldwide [2]. Each year 6000 people are newly diagnosed in the UK alone (Fig 1 [3]). But daunting figures and statistics aside, scientific advances have been made in HIV treatment, understanding of the disease has vastly improved, and laws have been put in place to protect people living with HIV. In fact, highly active antiretroviral therapy (HAART; Fig 3) has substantially transformed HIV infection from an inevitably fatal condition into a chronic disease with a longer life expectancy [3]. But, with prolonged treatment comes other problems such as tolerability, side effects, adherence to medication and drug resistance. Accordingly, strategies to optimise the therapeutic response, prevent adverse drug reactions, and find drugs with a novel action of mechanism must now come to the forefront of this enduring war between HIV and medicine.

Figure 1 New HIV diagnoses, AIDS and deaths over time; 1999-2014. If diagnosed early, people now living with HIV can expect a near-normal life span. People diagnosed with HIV late have a ten-fold increased risk of death in the year following diagnosis compared to those diagnosed promptly. In 2014, 346 were diagnosed with AIDS for the first time and 613 people with HIV infection were reported to have died, most of whom were diagnosed late. [3]

Figure 2 Thin sections of the entry of the HIV-1 virus into a CD4 + cell by fusion. The life cycle begins with the HIV virus recognising CD4 on the surface of the CD4+ T cells. (a) The virus is initially attached to the cell membrane. Several virus-cell interconnections (double-headed arrow) are seen between the virus and the cell membrane. It is thought that binding via a CCR5 or CXCR4 coreceptor [4] allows for gp41-mediated fusion of the virus with the host cell. (b) The Contact surface increases. (c) The envelope of the virus fuses to the cell membrane (double-headed arrow). Some virions (arrow) are tagged with ferritin (arrowheads). Fusion enables the reverse transcription of the viral RNA into DNA. For the viral DNA to integrate into the host genome, hydroxyl groups are added during 3’ processing, which is catalysed by the enzyme integrase. This complex of protein and viral DNA then can enter the nucleus, where the strand transfer reaction integrates the viral DNA into the host genome [5]. Virus replication occurs when the DNA in transcribed into both genomic RNA and mRNA. The mRNA is translated into multiple Gag-Pol polyproteins, the precursors to the structural proteins and enzymes of the virus, which cause migration to the plasma membrane. This allows for budding of the immature virions from the CD4+ T cell before they can then undergo maturation to form infectious viral particles. Scale bars indicate 100nm [6]

Figure 3 The HIV life cycle and antiretroviral drug intervention. Entry inhibitors interfere with viral entry into the host cell by inhibiting several key proteins that mediate the process of viron attachment, co-receptor binding and fusion [10]. Reverse transcriptase inhibitors include NRTIs, which are analogs of endogenous deoxyribonucleotides and high affinity for the viral reverse transcriptase. These are therefore incorporated into the viral DNA strand during synthesis and causes transcription termination as they lack the 3’-OH group necessary for phosphodiester bond formation in DNA strand elongation [11]. NNRTIs are compounds that bind to the allosteric site of the HIV-1 reverse transcriptase and interfere with its activity causing the selective block of HIV-1 transcription [9]. Integrase inhibitors bind cofactors needed for the interaction of integrase and the host DNA. This blocks the insertion of viral DNA into the host genome [12]. Protease inhibitors bind the active site of the viral protease with high affinity and as a result inhibits the cleavage of polypeptides necessary for viral maturation after budding from the host cell [13]. Maturation inhibitors, similarly to protease inhibitors stop the processing of the HIV-1 polypeptides but do this by binding to the polypeptides themselves [14].
Blog written by Victoria Miller
Reference
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