1) HIV/AIDS has infected over 75 million people globally, with 37 million currently living with the infection. It spread from non-human primates like sooty mangabeys and chimpanzees to humans in the 1900s.
2) There are two main strains of HIV - HIV-1 and HIV-2. HIV progresses through different phases including acute infection, clinical latency, and AIDS. Diagnosis involves testing for HIV antibodies or RNA.
3) The HIV life cycle involves several stages that can be targeted by antiretroviral drugs, including entry, reverse transcription, integration, assembly and budding. Promising research is being done in stopping viral replication and developing gene and cell-based
3. Introduction :
• Infected more than 75 million
• 37 million living with infection
• Spread from non human primates
to humans sporadically throughout
1900 s
• 1980 did virus come into world
attention
2 main strains :
•Hiv -1
•Hiv -2
SIV smm - sooty mangabeys
SIV cpz - chimpanzees
7. The Hiv Life Cycle with drug target :
doi:10.1038/nrdp.2015.35
8. Treatments :
1. Stopping the replication of HIV
https://labiotech.eu/features/hiv-cure-2020-research-review/
9. 2. Shock and kill
http://mymedicinemission.blogspot.com/2013/03/adults-cured-after-hiv-baby.html
- Phase 1b/2a run by Berlin-based Mologen
- It was not successful at reducing the HIV reservoir.
- And a recent study has shown that currently available LRAs only activate
less than 5% of the HIV reservoir
10. 3. Gene therapy :
1 . Artificial T Cell Receptors
CCR5Δ32/Δ32haematopoietic stem-cell transplantation
“Berlin patient’’
diagnosed with HIV in 1995 .
Brown was diagnosed with acute myeloid leukemia (AML)
In 2007 underwent stem cell transplantation after unsuccessful
chemotherapy.
“ Essen patient’’
In this case ART was interrupted one week before allogeneic HSCT and rapid
viral rebound of a pre-existing minority HIV-1 variant, which was able to infect
cells
through the alternative CXCR4 coreceptor, was observed three weeks later.
Such pre-existing CXCR4 variants were not observed in the Berlin patient11.
http://defeathiv.org/berlin/
11. 2 . Intracellular Immunization
1. protein based therapies
2. RNA-based therapies.
1. Protein-based strategies
1. Trans-dominant negative proteins
an altered form of a viral or cellular protein that can inhibit
the normal function of its wild-type counterpart
e.g.-RevM10
2. Fusion inhibitors
a protein or peptide that affects the fusion process during
viral entry into the cell
e.g.-maC46
3. Intrabodies
recombinant antibodies expressed intracellularly
4. Intrakines
modified intracellular chemokines
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517133/
12. RNA-based therapies.
RNA-based strategies include
1. Antisense.
2. Ribozymes.
3. Aptamers.
4. small interfering RNAs (siRNAs).
5. short hairpin RNAs (shRNAs).
6. AgoshRNA design .
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517133/
13. References
1. Falkenhagen Alexander, Joshi Sadhna. Genetic Strategies
for HIV Treatment and prevention. Molecular Therapy:
Nucleic Acids Vol. 13 December 2018.
https://doi.org/10.1016/j.omtn.2018.09.018.
2. Jade Ghosn, Babafemi Taiwo, Saraya Seedat, Brigitte
Autran, Cristine katlama. HIV. Seminar. Published online
July 20, 2018 https://dx.doi.org/10.1016/S0140-
6736(18)31311-4
3. Explaining HIV and AIDS. https://www.who.int/hiv/data/en/
4. https://www.avert.org/global-hiv-and-aids-statistics
5. https://www.avert.org/professionals/hiv-around-world/asia-
pacific/india
6. World Health Organisation (WHO).
https://www.who.int/hiv/data/en/
7. http://www.aidsmap.com/HIV-1-and-HIV-2/page/1322970/
8. https://www.projectinform.org/glossary/hiv-structure-function/
During prototypic HIV infection, the transmitted virus first infects target cells in mucosal tissues and then spreads through the lymphoid system (eclipse phase). HIV RNA levels first become detectable after several days and then increase exponentially, reaching a peak a few weeks later, at which point the adaptive immune response results in partial control. HIV antibody responses are largely ineffective owing to rapid viral escape. A steady-state level (set point) of viraemia, reflecting complex virus–host interactions, is then established. HIV-mediated destruction of CD4+ T cells leads to immunodeficiency and chronic inflammation
One of the most advanced HIV treatments seeks to inhibit the virus’ ability to replicate its RNA and produce more copies of itself. A similar approach is commonly used to treat herpes infections, and although it doesn’t get fully rid of the virus, it can stop its spread.
The French company Abivax showed last year in a clinical trial that this approach has the potential to become a functional cure for HIV. The key to its potential is that it can target the reservoir of HIV viruses that “hide” inactive within our cells.
“Current therapies suppress the virus in circulation by inhibiting the formation of new viruses, but they don’t touch the reservoir. Once you stop, the virus comes back in 10-14 days,” says Hartmut Ehrlich, CEO of Abivax. “ABX464 is the first drug candidate ever shown to reduce the HIV reservoir.”
The drug, called ABX464, binds to a specific sequence in the RNA of the virus, inhibiting its replication. In a Phase 2a trial, several patients were given the drug in addition to antiretroviral therapy. Eight out of 15 patients treated with ABX464 showed a 25% to 50% reduction of their HIV reservoir after 28 days, compared to no reduction in those taking only antiretroviral therapy
ABX464 blocks viral replication by preventing the export of viral RNA from the nucleus to the cytoplasm in infected cells. This transport is normally mediated by a viral protein called Rev, and the activity of Rev is efficiently inhibited by ABX464. Never targeted before, Rev has been postulated of potential interest for HIV treatment for some time, but ABX464 is the first molecule under development aimed at inhibiting it. Jamal Tazi, senior author of the article, stresses that “ABX464 targets an event after the genetic material of the virus has been integrated in the cell. This way, ABX464 not only prevents the infection of new cells, but it is the only drug to date that can act on already infected cells and prevent the synthesis of new viruses.” He added, “Therefore the difficult-to-reach reservoir of infected cells remaining under current HIV therapy may become reachable.” ABX464 does not affect the physiological cellular RNA-processing in humans. This suggests that ABX464 is specific for HIV RNAs and does not influence the synthesis of human proteins. ABX464 does not lead to HIV mutants that become resistant to treatment. In contrast to all other anti-HIV drugs, ABX464 may be effective as a monotherapy
So far, however, this approach has not proven its potential in human studies. Last year, one of the most advanced trials testing this shock and kill approach — a Phase 1b/2a run by Berlin-based Mologen — reported that although the drug could help manage HIV infections, it was not successful at reducing the HIV reservoir. And a recent study has shown that currently available LRAs only activate less than 5% of the HIV reservoir.
What makes HIV so dangerous is that it attacks the immune system, leaving people unprotected against infections. But what if we could supercharge immune cells to fight back? That’s the reasoning behind immunotherapies.
Researchers in Oxford and Barcelona reported last year that five out of 15 patients in a clinical trial were clear of HIV for 7 months without antiretroviral therapy, thanks to an immunotherapy that primes the immune system against the virus. Their approach combines a drug to activate the hidden HIV reservoir with a vaccine that can induce an immune response thousands of times stronger than usual.
While they showed that immunotherapy can be effective against HIV, the results still need to be confirmed, as well as what makes some patients respond while others don’t.
Bill Gates has been strongly supporting the development of HIV immunotherapies. One of its investments is in Immunocore. This company in Oxford has designed T cell receptors that can seek and bind HIV and instruct immune T cells to kill any HIV-infected cells, even when their HIV levels are very low — as is often the case of the HIV reservoir cells. The approach has been shown to work in human tissue samples, and the next step will be to confirm whether it works in people living with HIV
But one of the most advanced immunotherapies at the moment is a vaccine being developed by the French InnaVirVax. The vaccine, called VAC-3S, stimulates the production of antibodies against the HIV protein 3S, making T cells attack the virus. “Our approach is totally different to other vaccines, which boost an HIV-specific response,” says Joël Crouzet, CEO of InnaVirVax. “We promote an immune recovery, so that the immune system as all the tools to better recognize and eliminate the virus.”
After completing a Phase 2a trial, InnaVirVax is now testing VAC-3S in combination with a DNA-based vaccine from the Finnish FIT Biotech, which both parties expect could lead to a functional cure.
diagnosed with HIV in 1995. After controlling the virus for many years with antiretroviral therapy, Brown was diagnosed with acute myeloid leukemia (AML) and in 2007 underwent stem cell transplantation after unsuccessful chemotherapy. Of the HLA-matched donors, his Berlin doctors chose an unrelated donor who screened positive for the homozygous CCR5∆32 mutation. Despite enduring complications and undergoing a second transplant from the same donor in 2008, the outcome was ultimately a success. Nearly eight years after his transplant, Brown remains free of both his cancer and readily detectable HIV.
A single proof of concept was provided by the so-called “Berlin patient,” who remained free of detectable HIV after receiving a bone marrow transplant from a CCR5-Δ32 homozygous donor [8,9]. This genetic defect could be mimicked in a gene therapy setting. HIV mainly targets CD4+ T cells by binding to the CD4 molecule as well as a chemokine co-receptor, usually CCR5 or CXCR4, on the cell surface. In addition macrophages, monocytes, and dendritic cells can be infected by HIV.
In essen case, ART was interrupted one week before allogeneic HSCT and rapid viral rebound of a pre-existing minority HIV-1 variant, which was able to infect cells through the alternative CXCR4 coreceptor, was observed three weeks later. Such pre-existing CXCR4 variants were not observed in the Berlin patient11. Three other cases transplanted with wild-type CCR5 cells experienced viral rebound 12, 32 or 41 weeks after ART interruption despite a considerable reduction of the HIV reservoir12,13. We report an individual diagnosed with HIV-1 infection in 2003, with a CD4 nadir of 290 cells mm−3 and a baseline HIV-1 plasma viral
load of 180,000 copies per ml. ART
The viral replication cycle is arbitrarily divided into two stages: the early stage refers to the steps of infection from cell binding to the integration of the viral DNA into the cell genome, whereas the late stage begins with viral gene expression from the integrated provirus and leads to the release of the immature virions that subsequently mature into infectious particles (for further details, see the Figure legend).
RevM10 is a trans-dominant Rev mutant that interferes with the normal Rev function and thereby prevents the export of unspliced genomic HIV RNA from the nucleus to the cytoplasm [18,19,20]. Cells expressing RevM10 were shown to have a survival advantage in HIV-infected individuals, but no substantial impact on the viral load was observed
Recently, promising results were obtained with a fusion inhibitor based on a 46 amino acid domain of the HIV-1 Envelope gp41 protein (C46) that prevents membrane fusion [35]. The C46 peptide has also been stably expressed as a membrane-anchored peptide (maC46) that was able to inhibit replication of a broad range of HIV-1 isolates [36,37]. The safety of maC46 has been confirmed in a phase I clinical trial in which autologous T cells, transduced with a retroviral vector expressing maC46, were infused into patients [38]. However, the in vivo antiviral effect remains currently unknown.
To date numerous antisense RNA molecules have been designed to target HIV-1 mRNAs in a sequence-specific manner, resulting in the formation of non-functional RNA duplexes that are subsequently destroyed
