AIDS: Incidence and mortality
Infection with the human immunodeficiency virus (HIV) causes chronic, life-threatening disease, called acquired immunodeficiency syndrome (AIDS). Infection can occur by sexual contact, blood transfusions, needle sharing, or even maternal transmissions (blood-borne virus or in breast-milk). HIV attacks the immune system by destroying certain types of white blood cells: CD4+ lymphocytes. These cells defend the body against infection, cancers or other disease. Thus, when HIV destroys CD4+ lymphocytes, it interferes with the body's ability to fight infectious organisms. Many of the complications of HIV infection, including death, are usually the result from other infections.
Since its discovery, HIV has been a great burden to global wealth and health, causing over 1 million deaths in 2015[1]. According to the latest WHO statistic report, the number of people living with HIV is 37.7 million[2]. However, major investments and improvements in AIDS, programs have led to decreased incidence and mortality. Indeed, in 2020, a wider availability of antiretroviral therapy has reduced the number of AIDS-related deaths by 55% between 2000 and 2020[3]. Indeed, as of 2020, the FDA has approved 222 antiretroviral drugs for global HIV/AIDS Relief[4] many of them taken together to stop HIV from reproducing. However, these cannot eliminate the virus, which persists in an inactive form.
Mechanism of infection
HIV is a retrovirus, which means its genetic information is stored as RNA (ribonucleic acid). Like all viruses, it replicates using the cells machinery, like CD4+ lymphocytes[5]. The virus attaches to the CD4 protein expressed on certain cell surfaces (macrophage, dendritic cells, lymphocytes) using its envelope protein gp120. This creates a shift in the conformation of gp120 allowing HIV-1 to bind to a co-receptor CCR5 or CXCR4 (1). This permits a fusion between the virus and the cell membrane (2) allowing the HIV to release its RNA into the cell. The RNA is then converted to DNA (3) (with a viral enzyme called reverse transcriptase) and the produced DNA can then migrate to the nucleus where it can be integrated in the cell’s DNA (4). Using the cell machinery, the infected cell can now produce viral DNA which is transcribed to RNA (5) and translated (6) into viral proteins, before being assembled (7) to form a new virus released (8) in the blood stream to infect new cells[6] - see figure below.
Antiretroviral drugs - used to treat HIV infection - inhibit the three enzymes essential for the virus life cycle (reverse transcriptase, integrase, and protease) that the virus uses to replicate or to attach to and enter cells[7].
Recently, it has been described that a small number of people who contract HIV can live with the virus without needing treatment. These people are known as “HIV controllers”. These people, have a low expression of CCR5 which protects CD4+ lymphocytes cells from viral entry[8]. Indeed, these specific controller CD4 + T cells show decreased susceptibility to CCR5-dependent HIV entry, suggesting that genetic and functional regulation of the coreceptor CCR5 can help naturally control HIV infection. Indeed, with this protective mutation, 3 patients have been cured.
AIDS remissions
Today, 3 case studies of AIDS remission have been described worldwide, using an innovative treatment
o The Berlin Patient in 2008
o The London Patient in 2019
o The New York Patient in 2022
The Berlin Patient
The patient, Timothy Ray Brown[9], suffered from leukemia. His immune system is destroyed with chemo or radiotherapy to eliminate immune cells infected with HIV despite effective antiretroviral treatment. Then, he received a stem cell transplant with HIV-protective mutation (the donor had a mutation in the CCR5 gene) which blocked HIV entry. The patient was declared cured of HIV and leukemia and stayed in remission for 12 years until he died of cancer
The London Patient
The patient[10], Adam Castillejo, had Hodgkin lymphoma and also received a stem cell transplant with HIV-protective mutation in the CCR5 gene and was cured of HIV and lymphoma, confirming that Mr. Brown’s case was not an accident.
The New York Patient
The New York patient, a woman[11] who was diagnosed with acute HIV infection and myeloid leukemia has been in remission from both diseases for 14 months after receiving an experimental stem cell transplant procedure. The cutting-edge stem cell transplant method replaces an individual’s immune system with another person’s, treating their cancer while also curing their HIV infection[12].
After her immune system was destroyed to eliminate infected immune cells, she received a dual stem cell graft (from a half-matched adult related donor and umbilical cord cells which have the protective against HIV CCR5 mutation) banning new viral copies to enter and infect any other immune cells.
The variant Δ32 of the CCR5 mutation (also called CCRΔ5/Δ32), which appears to be very effective against HIV, is extremely rare. It is only found in 1% of the general population, which makes it difficult to use it as a treatment because of the lack of scalability. However, this should not lessen the hopeful and positive outcome of this case.
“Despite of feasibility challenges, this new HIV remission case is very exciting news and will continue to energize the HIV cure research agenda, reminding us of its potential to beat HIV,” said Dr Meg Doherty, Director of WHO’s Global HIV, Hepatitis and STI Programs.
As a result of the mRNA push made by COVID vaccines, researchers are now testing mRNA HIV vaccines. It seems that after decades of inevitable death, potential cures for HIV are closer than ever.
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References
[1] Kazuhisa Yoshimura, Journal of Infection and Chemotherapy, V 23, Issue 1, Pages 12-16, (2017) [2] https://aidsinfo.unaids.org/ [3] https://cdn.who.int/media/docs/default-source/gho-documents/world-health-statistic-reports/worldhealthstatistics_2022.pdf?sfvrsn=6fbb4d17_3 [4] https://www.fda.gov/drugs/human-immunodeficiency-virus-hiv/hiv-treatment [5] Created with BioRender.com [6] Moir S, et al., Annu Rev Pathol.; 6:223-48. 2011 [7] https://www.fda.gov/drugs/human-immunodeficiency-virus-hiv/hiv-treatment [8] Claireaux, M., et al. Nat Commun 13, 521 (2022) [9] Hutter G et al. N Engl J Med; 360: 692-698 ; 2009 [10] Gupta RK et al. Nature ; 568 : 244-248, 2019 [11] https://www.nih.gov/news-events/news-releases/researchers-document-third-known-case-hiv-remission-involving-stem-cell-transplant [12] https://clinicaltrials.gov/ct2/show/NCT02140944?term=NCT02140944&draw=2&rank=1