Content Reviewers:Antonella Melani, MD
Two people come to the infectious disease clinic. The first one’s David, a 42 year old man who has a fever, associated with a cough and difficulty breathing. David mentions that he’s HIV-positive, so you decide to run a blood test, which reveals an alarming T cell count of 180 cells / mm3. You immediately ask for a chest X-ray, which shows gray hazy-looking areas in both lungs. Next comes Charles, a 32 year old man. Charles was referred to the clinic by his dentist, who detected white plaques on both sides of his tongue. When you try to scrape the plaques with a tongue depressor, you realize that they can’t be removed. Upon further questioning, Charles tells you that lately he’s been losing a ton of weight, although he hasn’t been exercising or dieting at all. You decide to ask for an HIV-1/2 antigen/antibody immunoassay, which turns out positive. Okay, now both David and Charles have HIV, which stands for human immunodeficiency virus. HIV specifically targets the cells of our immune system, leading to progressive immunodeficiency, which is when the immune system begins to fail gradually. Ultimately, affected individuals can develop AIDS, or acquired immunodeficiency syndrome. What’s important to note is that AIDS puts at increased risk of certain opportunistic infections or tumors that a healthy immune system would usually be able to fend off.
Now, HIV can be transmitted via certain bodily fluids from an infected person, including blood, genital fluids like semen or vaginal discharge, and breast milk. However, HIV is not present in saliva, sweat, urine, or feces. Now, to contract the infection, these bodily fluids need to come into direct contact with a healthy person's blood, broken skin, or mucosal surfaces.
The most common means of transmission is horizontal via sexual intercourse, especially via male-to-male transmission, but also male-to-female and female-to-male transmissions can occur, while female-to-female transmission of HIV is quite rare. The next most common means of horizontal transmission involves direct blood-to-blood contact, which, remember, is most common among intravenous drug abusers who share needles. Less commonly, blood-to-blood contact can occur via accidental needlestick injuries, or by transfusing blood products from an infected donor. To prevent this, blood donations are always screened for infections like HIV, among others. Finally, for your exams, you must absolutely know that HIV can also be passed via vertical transmission, which means that a pregnant individual can transmit the infection to their child before birth via the placenta, as well as during delivery via blood or genital fluids, and afterwards via breast milk. And that’s very high yield!
All right, now there are two distinct types of HIV: HIV-1 and HIV-2. Although they’re basically the same, keep in mind that HIV-1 is more common, while HIV-2 is less infectious and thus less common. Now, regardless of the type, the viral structure is the same. HIV is a single-stranded, positive-sense, enveloped RNA retrovirus. HIV has a diploid genome, which means the virus has two copies of positive-sense single-stranded RNA. Within this RNA, there’s the genes that contain all the necessary information to synthesize the viral enzymes and structural proteins within the infected cells.
For your exams, there are three main genes you need to remember. The first one’s the gag gene, which codes for two important structural proteins. One is the capsid protein p24, and the other one is the matrix protein p17. Then there’s the pol gene, which codes for enzymes like reverse transcriptase, integrase, and protease, which we’ll cover in a bit. Finally, the env gene codes for the glycoprotein gp160, which is then cleaved by the protease to form two envelope glycoproteins: gp120 and gp41.
Now, once HIV enters the bloodstream, it targets CD4+ cells, which are immune cells that have this specific protein called CD4 on their membrane. For your exams, the main CD4+ cells to remember are T-helper cells and macrophages. Normally, the CD4 protein helps these cells communicate with other immune cells in order to trigger an immune response against foreign pathogens. So this little protein is pretty important for our immune system, but it’s also HIV’s main receptor. In fact, HIV attaches to the CD4 protein via the glycoprotein gp120 found on its envelope. But remember that this is not enough to get inside the cell; gp120 also needs to bind to a coreceptor. During early infection, the most common coreceptor that HIV uses is the membrane protein CCR5, which is typically found on T cells and macrophages. On the other hand, during late infection, HIV tends to switch to the membrane protein CXCR4, which is mainly found on T cells.
Now, for your exams, you must absolutely know that some people have a mutated CCR5 gene. Heterozygous mutations typically result in the expression of fewer CCR5 proteins on the host cells, which makes it harder for the virus to infect them. As a result, these individuals present with a slower disease progression. On the other hand, individuals with homozygous mutations don’t express any CCR5. As a result, HIV can’t infect their cells, so these individuals are resistant or immune to HIV. Unfortunately, CCR5 mutations aren’t that frequent.
Now, for those without this mutation, once gp120 binds to CD4 and either CCR5 or CXCR4, the glycoprotein gp41 is exposed and anchors to the cell membrane. This allows the viral envelope to fuse with the cell membrane, and the virus is able to inject its RNA and enzymes into the cell. Once inside the cell, the enzyme reverse transcriptase uses this viral RNA to synthesize a complementary double-stranded piece of “proviral” DNA.
Then, this proviral DNA enters the host cell’s nucleus, where the enzyme integrase helps it integrate into the host cell’s DNA. As a result, whenever the host cell transcribes and translates its own DNA into RNA and proteins, it will end up inadvertently transcribing and translating HIV’s RNA and proteins too! Pretty sneaky, huh? Ultimately, new HIV viruses are assembled and bud off from the cell membrane to infect more cells.
One important thing to be aware of is that HIV tends to make tons of errors when it replicates. As a result, the virus can rapidly acquire mutations that create various HIV strains, which contain slightly different viral enzymes and structural proteins. Now, the reason why this is so important is that it allows the virus to evade the host’s immune response, as well as develop resistance to treatment. And that’s a high yield fact!
Okay, now if HIV infection is left untreated, it will progress over time, resulting in four clinical stages. The first one is the acute stage, which starts as soon as the individual gets infected. Most often, this initial or primary infection is mediated by the R5 strain of HIV, which uses the CCR5 coreceptor to infect macrophages and T cells near the infection site. What’s important to note here is that, during this initial period, the individual is already infectious, but the virus hasn’t replicated enough to be detectable via HIV tests. So, during this initial period of time called the window period, individuals who get tested can get a false negative result. For your exams, remember that the window period for HIV usually lasts about 1 month, but it can range between 10 days to 3 months.
Now, during this window period, infected cells start migrating from the infection site to the lymph nodes, where a lot of immune cells live. This leads to a big spike in HIV replication, while the T cells decline dramatically. At a certain point, the virus replicates so much that the window period ends, and HIV tests are able to detect the infection. Now, HIV replication continues to increase until it peaks at about week 6 from the primary infection. At this point, individuals may begin to experience flu-like or mononucleosis-like symptoms, such as fever, fatigue, lymphadenopathy or swollen lymph nodes, and joint or muscle aches. These symptoms typically last for about 2 weeks, during which the immune system mounts a counterattack, and starts to control the amount of viral replication. As a result, the viral count declines, while the T cells rise again. This trend usually continues until month 2; during this period, the T cell count usually remains at a normal level, over 500 cells / mm3.
As the virus declines, the HIV infection enters its second stage, which is the chronic or clinically latent stage. And this stage can last anywhere between 2 to 10 years. Now, during this stage, the T cell count usually remains at a level that’s between 350 and 500 cells / mm3, so the affected individual can still fight off other infections and initially remain asymptomatic. However, bear in mind that the virus keeps slowly replicating in the lymph nodes, while T cells gradually decrease. As a consequence, the immune system progressively weakens, and some latent or dormant infections can reactivate. A very common one is herpes simplex virus, which causes herpes with painful oral blisters or genital ulcers and pustules; as well as varicella-zoster virus, which may lead to shingles, with painful vesicles that are typically located along one dermatome. Another very high yield latent pathogen is mycobacterium tuberculosis, which causes a pulmonary disease called tuberculosis. In addition, people living with HIV are more susceptible to develop community-acquired pneumonia, and for your exams, remember that the most common cause is Streptococcus pneumoniae.
Now, remember how HIV replication can create viral mutations? Well, during the clinically latent stage, some individuals may develop an X4 strain of HIV that targets the CXCR4 coreceptor, which is essentially only on T cells. These X4 strains kind of lay low in the lymphoid tissues, and steadily destroy CD4+ T cells as the viral count increases.
That leads to the third stage of HIV infection, or the symptomatic stage. At this point, the body’s T cells drop low enough, between about 200 to 350 cells / mm3. As a consequence, individuals become moderately immunocompromised, and may start developing relatively minor infections. Among the most frequent ones, there’s oral thrush, also known as oral candidiasis, which is a scrapable white plaque caused by the yeast Candida albicans.
The diagnosis can be confirmed upon microscopy on a smear sample, where the most high yield finding is the presence of pseudohyphae. This is when candida cells have an elongated shape that looks like long thin filaments. Another similar lesion is oral hairy leukoplakia, which is a hairy-looking white plaque on the side of the tongue caused by Epstein-Barr virus. To set these two white plaques appart, the main difference is that hairy leukoplakia is unscrapable. And that’s a high yield fact! Another characteristic condition at this stage is Kaposi sarcoma, which is a malignant tumor of the skin and soft tissues that’s caused by the human herpesvirus 8, or HHV-8. What’s important to note is that, upon a punch biopsy, you’d find lymphocytic inflammation, meaning that the skin is infiltrated with lymphocytes. Finally, individuals at the symptomatic stage often develop malignant lesions from infection by the human papillomavirus, or HPV. These include squamous cell carcinoma of the anus in males and cervix in females.
As the viral count continues to increase, more T cells are lost. Ultimately, individuals reach the fourth stage of HIV infection, called AIDS, which is when the T cells fall below 200 cells / mm3. At this point, individuals become severely immunocompromised and may present with persistent fever, fatigue, unintentional weight loss, and diarrhea. In addition, having a T cell count below 200 cells/mm3 puts the affected individual at risk for some serious “AIDS-defining” conditions, such as certain tumors or opportunistic infections that a healthy immune system would typically be able to fend off. Ultimately, many people with HIV infection die from these conditions.
A very high yield “AIDS-defining” condition is histoplasmosis, which is caused by the fungus Histoplasma capsulatum. Most individuals with histoplasmosis experience fever, weight loss, and fatigue, as well as cough, and dyspnea. In addition, some individuals may present with diarrhea, nausea, and vomiting. For diagnosis, the most high yield feature seen with a peripheral blood smear are oval yeast cells within macrophages. Another AIDS-defining condition is pneumocystis pneumonia by the fungus Pneumocystis jirovecii. This condition also presents fever, weight loss, and fatigue, as well as cough, and dyspnea. So to differentiate it from histoplasmosis, a key finding on chest imaging that should make you think of pneumocystis are “ground-glass” opacities, which are gray hazy-looking areas in the lungs. So be sure to keep an eye out for this clue!
Another very frequently tested AIDS-defining condition is progressive multifocal leukoencephalopathy, which is caused by the JC virus. Keep in mind that JC virus can be found latent in most people, since a healthy immune system can keep it under control, but it can reactivate in case of severe immunosuppression. Now, progressive multifocal leukoencephalopathy is a demyelinating disease that affects multiple locations of the brain and worsens over time. Symptoms typically include progressive motor and cognitive neurologic symptoms like weakness, clumsiness due to lack of coordination, speech difficulties, and dementia. Diagnosis of progressive multifocal leukoencephalopathy can be confirmed via MRI, where the demyelination can be spotted as non enhancing areas. Finally, a very important AIDS-defining condition is HIV-associated dementia, which occurs when the virus spreads to the brain. These individuals present with an altered mental status, as well as cerebral atrophy, which can be seen on neuroimaging.
But there’s more! Over time, as the T cell count falls below 100 cells/mm3, individuals become severely susceptible to opportunistic infections. One of them is aspergillosis, a lung infection that’s caused by the fungus aspergillus fumigatus. Symptoms include hemoptysis or coughing up blood, and pleuritic chest pain, as well as fever, cough, and dyspnea. A very high yield fact for diagnosis is that chest imaging can reveal pulmonary infiltrates and cavitation due to tissue necrosis.
Another big one is cryptococcosis. This is caused by inhaling the fungus Cryptococcus neoformans, which is typically found in soil and bird droppings. Rarely, the infection can affect the lungs, which is known as pulmonary cryptococcosis. However, in severely immunocompromised individuals, the infection may disseminate or spread to the brain, causing cryptococcal meningitis. Affected individuals may experience symptoms like headache and sensitivity to light, as well as nausea and vomiting. If cryptococcal meningitis is suspected, diagnosis can be confirmed using an India ink stain of the cerebrospinal fluid. And because cryptococcus neoformans is an encapsulated yeast, this stain allows to see a clear halo around the yeast cells. In addition, a latex agglutination test can be used to detect the characteristic polysaccharide capsular antigens.
Another opportunistic infection that may hit the brain is toxoplasmosis, which is caused by the parasite Toxoplasma gondii. Individuals usually get infected from contact with cat feces, as well as consumption of undercooked meat, especially pork and lamb. In severely immunocompromised individuals, toxoplasma may spread to the brain, causing cerebral toxoplasmosis. This may present with a headache, fever, and neurologic symptoms like weakness, speech difficulties, and seizures. Now, cerebral toxoplasmosis is characterized by multiple brain abscesses. So in a test question, a big clue for the diagnosis would be a CT scan or MRI showing multiple ring-enhancing lesions with central necrosis.