HIV Infections and AIDS: Historical Development and Therapeutic Strategies

Valentina Zanin and Prof. Guido Poli on HIV/AIDS

Valentina Zanin Prof. Guido Poli Basics Mechanisms of Disease, GP11 15/12/2023 HIV infections and AIDS Before the start, the professor pointed out that the last lessonof the course on Tuesday 19th will be dedicated to Q&A immunology.

Historical Development of HIV/AIDS

In 1981, we had the very first cases of a new disease that became universally known in the Western world. Since then, there have been incredible achievements, particularly concerning therapy as well as basic knowledge.We're still facing two major obstacles: the absence of a vaccine and the techniques to eliminate the virus from an infected person. There is not much talking about HIV AIDS in the media, it's sort of a forgotten disease. To quote Dan Brown in Angels and Demons, the most dangerous enemy is the one that nobody fears. That's also the current issue with COVID, when there are currently hundreds of people dying every week from it.

Understanding AIDS: Acronym and Causative Agent

AIDS is an acronym. It stands for Acquired Immunodeficiency Syndrome. It was first described in 1981. Between 1983 and 1984, the virus was first identified. The following year it was proven to be the causative agent of AIDS.AIDS is exclusively caused by a retrovirus. Since we talked about congenital immune deficiencies in the previous lessons, it's important to add that there is a genetic disease which is called CD4 T cell lymphocytopenia (lymphopenia) or known HIV-causing AIDS. It is a genetic condition that reproduces most of theimmunological features associated with HIV infection. In 99.9% of the cases, the clinical features of age are caused by HIV infection. There is a very minor fraction of cases that are on a genetic basis, which more or less reproduces some of the essential features of aging. This will be added to the next lesson.

Syndrome Definition and HIV

As previously discussed, the term syndrome refers to symptoms siding together, used whenever we don't have a specific cause, and cases in which multiple causes converge into a common feature. For example, now that we are in the winter season. Many of us are suffering from a flu-like type of syndrome. It's called a syndrome because to prove that you get flu, you would need to do a swab and molecularly or immunologically find that the symptoms are indeed caused by the influenza virus, whereas we have many other flu-like viruses, lots of paramyxoviridae viruses, parainfluenza , which can give you the same symptoms. Q: In the case of HIV, with the exception of the genetically based CD4T cell lymphopenia, we have a single cause. So why is AIDS named as a syndrome and not a disease? A: Because the term AIDS remains a sort of historical benchmark. And the virus is HIV, the human immunodeficiency virus.

Global Impact and Prevalence of HIV

The numbers from the lecture's slides are slightly changed (they weren't updated). It's about 70 million or 79 million people who have been infected worldwide. Nowadays there are 38- 39 million people living with HIV, 75% of whom receive antiretroviral therapy. Their lifespan is significantly prolonged compared to the past. The region in which HIV AIDS remains a major problem for healthcare, and a major cause of death, is Sub-Saharan Africa, in particular South Africa (the nation with the highest prevalence of HIV infection). About one out of four people in Germany are infected with HIV. Page 1 of 15Valentina Zanin Prof. Guido Poli Basics Mechanisms of Disease, GP11 15/12/2023 In Italy, there are around 150,000 infected people. The incidence, meaning the number of new diagnoses per year, went down during the pandemic period because people had lessphysical relationship with each otherand now it's picking up again. As of today, circa 3,000 new cases per year in Italy. The very problem that we have in Italy and in other similarly civilized countries remains the fact that people discover to be infected only once they get sick. In some cases, they have frank AIDSand these people have up to nine years of unknown infection. They could spread the infection to their wives or husbands, through sexual contact of some kind. This remains the main problemfrom an epidemiological or public health point of view.

Therapeutic Approaches and Challenges

There are effective therapies. These patients aren't diagnosed with an advanced disease. They can be rescued in most cases. But in the meanwhile, they have contributed to spreading the virus around society. On December 1st every year, we celebrate World AIDS Day, the fight against AIDS. In Italy and many other countries, there are free antiretroviral therapies. This is not the case for other countries, including the United States, for example, in which we have to pay or need to have specific insurance. An additional issueis the prevalence of drug-resistant mutations, whichare much higher in the States than in Italy, simply because in the Statesthis therapy isusually administered by GP, by general practitioners, not necessarily through IB specialists. And so, the monitoring is much less rigorous on a general population base. Obviously, we're talking about a much bigger population in a much bigger country. So, combination antiretroviral therapy or C-ART is extremely effective, even in people with advanced disease, in blocking virus replication, blocking disease progression, and inducing a good level of immunological reconstitution. But it fails in terms of elimination of infection. It's a retrovirus, so it integrates its genome into the host cell genome.

Role of CDC in Epidemiological Surveillance

The CDC, the Centers for Disease Control, which is based in Atlanta, it's a U.S. government institution together with the NIH (NIH being dedicated mostly to research), FDA, and the Food and Drug Administration (which is mostly dedicated to patenting and approval). The CDCis mostly dedicated to epidemiological surveillance of everything, from nuclear outbreaks to motor car accidents, including, of course, outbreaks of infections of any nature, particularly on US soil.

Early Cases and Identification of AIDS

Morbidity and Mortality Weekly Report (MMWR)

Morbidity and Mortality Weekly Report (MMWR) Going back to the beginning on June 5,1981, the release of AIDS was not even a scientific paper, it was more of a bulletin called Morbidity and Mortality Weekly Report, MMWR. They described that in the period between October 1980 and May 1981, five young men, all active homosexuals, were treated for biopsy-confirmed pneumocystis carinii pneumonia (PCP). Pneumocystis carinii, that has been renamed later as pneumocystis jiroveci (PJP), is a very common microbe that doesn't give any sort of pathology in people with a normal immune system. It was very common to find, so the fact that they had interstitial pneumonia caused by PCP, pneumocystis carinii pneumonia, immediately suggested that these people who shared the young age and the fact of being a male homosexual had a profound defect in the immune system. This was also reinforced by the fact that they had other infections Page 2 of 15Valentina Zanin Prof. Guido Poli Basics Mechanisms of Disease, GP11 15/12/2023 typically associated with immunodeficiency, such as cytomegalovirus infection, Candida albicans, mucosal infection, etc. Since most of these patients died, therewere reports first in LA and later in San Francisco, then in New York.The fact that the first evidence came from homosexual mena lot of speculation about their sexual habits. But then, immediately became another group of people, particularly hemophiliacs. Hemophiliacshave a genetic defect in factor VIlland needed at that time to be infused with that coagulation factor. The infusions are derived by hundreds of liters of blood donors' plasma. Since blood donation was rewarded with pay, a lot of intravenous drug abusers, as well as other categories, were admitted to the block. Intravenous drug abuser was another category that became immediately affected by this disease. It was very clear after a few months that this was not a strictly gay disease. Media- wise, in the early 90s, there was the very famous case of Magic Johnson, one of the most famous basketball players in the world. He declared to be seropositive at the time declaring that he had a relationship with a lot of women. From that point on, his was not a gay man- restricted type of infection.

HIV Infection: A "Poverty-Related Disease" (PRD)

HIV-AIDS Pandemics (data from 2013)

HIV Infection: A "Poverty-Related Disease" (PRD - Together with Malaria and TB) Another important aspect is to HIV-AIDS Pandemics (data from 2013) Color: 40 Lesotho Botswana acknowledge the fact Zimbabwe Namibia Swaziland . 20 Mozambique Zambia Size: that this is a disease 10 Malawi Number of people living with HIV South Africa Tanzania Kenya 1 000 000 that affects Central African Rep. Cameroon Uganda 500 000 100 000 5 000 000 4 Cote d'ivoire Chad Congo, Rep luge · Ovyan 50 000 . Equatorial Guinea Updates & sources: . (Sources: UNAIDS / WHO and offers ) Ethiopia Rwanda Bahamas 2 la Nigeria 1.7 Dominican Pen.O < 10 000 Angola Brass und tilbage Brazi @Mousitus Sudan Ukraine ailand www.gapminder.org/hiv particularly people in poor countries. The 1 RULO Moutong france OD Salvador Venezuela WHO put together United States Poru Paraguay Colombia Switzerland Algernif Porugal Uruguay Malayin Spain 0.4 MILLION DIED Costa Rica Canada this definition of cuado Mexico 0.2 united Enosom Nicaragua ndonesia Alebojan Ausbolo singapore poverty-related 0.1 In 2011, 1.7 million people Morocco Lacanon #NOIWOY worldwide died from China Cuba @ Poland . Moita Friand Sweden diseases, which AIDS-related causes, down Mongallo Hungary New Zealand Soud MODA 0.04 24% from the peak in 2005. HIV infected (% of adults aged 15-49 years) Cope vings HO Tino la Philippinet Ciech tep. " Hovgs top. ... Croato Japon group together HIV, 50 000 500 1 000 2 000 5 000 10 000 20 000 AIDS, malaria, and Income per person ($ per year in purchasing power parity) tuberculosis. Of course, also other diseases, but these are the three major ones. In this graph, there isthe number of infected people on the y-axis and the income per person, which is a parameter of the wealth in a certain state. The highest number of infected people are in countries with a very, relatively poorincome per person. The partial exception is South Africa. South Africa is the single nation with the highest number of infected individuals compared, for example, to the US. But South Africa, as you know, is made of two very distinct populations, the whites and the blacks. The infection is particularly prevalent among the black population.

Routes of HIV-1 Transmission

Routes of HIV-1 Transmission After a few years, it became clear how HIV infections are spread, mostly from unprotected sex with a seropositive person and the other route if you get infected blood or blood product, which is particularly of interest for transmission among intravenous drug users, which exchange needles and syringes. This is also important to keep in mind for you also future MDs, that a needle stick by itself has a very low likelihood of transmission of the virus. The virus is not easily transmitted, contrary to what one would think. If instead of the needle, you have around 1 cc of blood, the likelihood of transmission it's up to over 90%. Everybody who