Leukemia (Blood Cancer)

        

 HIV, or human immunodeficiency virus, is a virus that targets cells in the immune system. Over time, the immune system begins to fail which is called immunodeficiency, and this increases the risk of infections and tumors that a healthy immune system would usually be able to fend off. These complications are referred to as AIDS or acquired immunodeficiency syndrome.

Now there are two distinct types of HIV—HIV-1 and HIV-2.

 

HIV-1 is the more commonly associated with AIDS in the US and worldwide, HIV-2 is rarer, and typically restricted to areas in western Africa and southern Asia. HIV-2 is so uncommon that “HIV” almost always refers to HIV-1. Alright HIV targets CD4+ cells, meaning cells that have this specific molecule called CD4 on their membrane. Macrophages, T-helper cells, and dendritic cells are all involved in the immune response and all have CD4 molecules; therefore they can be targeted by HIV. The CD4 molecule helps these cells attach to and communicate with other immune cells, which is particularly important when the cells are launching attacks against foreign pathogens. So this little molecule is pretty important for our immune system, but it’s also extremely important for HIV. HIV targets and attaches to the CD4 molecule via a protein called gp120 found on its envelope. HIV then again uses gp120 to attach to another receptor, called a co-receptor. HIV needs to bind to both the CD4 molecule and a co-receptor to get inside the cell.

The most common co-receptors that HIV uses are the CXCR4 co-receptor, which is found mainly on T-cells, and the CCR5 co-receptor which is found on T-cells, macrophages, Monocytes, and dendritic cells. These co-receptors are so important that some people with homogeneous genetic mutations in their CCR5 actually have resistance or immunity to HIV since HIV can’t attach and get into the cell. In fact, even heterozygous mutations which lead to fewer co-receptors on the cells can make it harder for the virus to spread and results in a slower disease progression. For those without this mutation though, once HIV binds to CD4 and either CCR5 or CXCR4, it gains access to the cell.

HIV is a single-stranded, positive-sense, enveloped RNA retrovirus, meaning that it injects its single strand of RNA into the T-helper cell. The “retro” part of a retrovirus isn’t referring to its style but refers to its need to use an enzyme called reverse transcriptase to transcribe a complementary double-stranded piece of “proviral” DNA. Proviral just means that it’s ready to be integrated into the host’s DNA, so it enters the T-helper cell’s nucleus and pops itself into the cell’s DNA, ready to be transcribed into new viruses, pretty sneaky. Well here’s the actual sneaky part—when the immune cells become activated, they start transcribing and translating proteins needed for the immune response. Ironically, this means that whenever the immune cell is exposed to something that causes it to start up an immune response, like any infection, the immune cell ends up inadvertently transcribing and translating new HIV viruses, which bud off from the cell membrane to infect more cells.

Very sneaky indeed! One thing to know is that HIV is notorious for making errors when it replicates and that during an infection it can mutate to create slightly different strains of viruses. These viruses are all still considered “HIV” but behave slightly differently from each other and target different cells in the host, in fact, that host cell preference is called viral tropism. So let’s start with HIV entering the body through sexual intercourse which is how it typically spreads from person to person. At this early point, during what we call acute infection, the R5 strain of HIV, which binds to the CCR5 co-receptor, will get into macrophages, dendritic cells, and T cells. Usually, dendritic cells hanging out in the epithelial or mucosal tissue where the virus entered the body, capture the virus, and migrate to the lymph nodes, where a lot of immune cells live, and the R5 strain of HIV essentially has a field day, infecting T-helper cells, macrophages, and more dendritic cells, which leads to a big spike in HIV replication and the amount of virus found in the patient’s blood.

Patients typically experience flu-like or mononucleosis-like symptoms during acute infection. In response, the immune system mounts a counterattack and starts to control the amount of viral replication, and the amount of virus in the blood declines to lower but still detectable levels by 12weeks—at which point the patient enters the chronic or clinically-latent phase, which can last between 2 and 10 years. If we also plot the amount of T cells alongside the amount of virus, we’ll see that they loosely mirror each other, which makes total sense. Initially, you have a considerable decline in the acute phase until the immune system mounts its counterattack. After this point, even though there may not be any clinical signs or symptoms of the virus, the virus is steadily chipping away at the immune system, and the number of viruses in the blood slowly increases, while at the same time T cells slowly decrease, losing about 1-2billion T cells every day. During this chronic phase, T cell counts usually remain above 500cells/mm3, about the size of the head of a pin, and patients can still fight off other infections fairly well, although some infections like tuberculosis become more common and severe.

Remember how HIV replication can create mutations? Well during the chronic phase of HIV infection, it’s worth pointing out that some patients develop an X4 strain of HIV which targets the CXCR4 co-receptor, which is essentially only T-cells. These X4 strains kind of lay low in the lymphoid tissues, and steadily destroy CD4 T cells since about 90% of T cells are found in lymphoid tissue. Not all patients develop the X4 strain, though, so it’s not completely clear what the presence of this strain implies about the disease course. When the body’s T cells drop low enough, between about 200 and 500cells/mm3, patients start experiencing symptoms like swollen lymph nodes, or lymphadenopathy, as well as relatively minor infections like oral hairy leukoplakia, a hairy-looking white patch on the side of the tongue caused by the same Epstein-Barr virus that causes mononucleosis, as well as oral candidiasis, a yeast infection in the mouth.

As more T cells are lost, and the level falls below 200cells/mm3, the immune system becomes severely compromised and at this stage, the condition has progressed from HIV disease to AIDS. At this point, people experience things like persistent fever, fatigue, weight loss, and diarrhea. And the HIV count in the blood might increase significantly. At this point, certain conditions start to develop that are said to be “AIDS-defining”, such as recurrent bacterial pneumonia, pneumocystis pneumonia, and fungal infections like candidiasis of the esophagus. Other conditions include certain tumors and malignancies like Kaposi sarcoma which causes lesions on the skin and other soft tissues, and primary lymphoma of the brain. Many people with AIDS die from infections that a healthy immune system would typically be able to fend off, like pneumocystis, cytomegalovirus, or mycobacterium avium complex.

Male-to-male transmission is the most common mode of transmission in the US, and male-to-female is the most common mode in resource-limited settings. Although less common, female-to-male transmissions occur as well since HIV is present in the vaginal and cervical fluids of infected women. In fact, over 75% of all cases of HIV are contracted from sexual intercourse. The next most common means of transmission include things like intravenous drug abuse and mother-to-child transmission, which can be via the placenta during delivery, or via breast milk. Other, much less common modes of transmission include accidental needle-sticks and the use of blood products like blood transfusions. As far diagnosis goes, there are a few types of HIV tests that can be done—antibody tests, antibody/antigen tests, and RNA/DNA tests. Antibody tests look for antibodies that the body’s made against HIV. Antigen tests look for the virus directly, so antibody/antigen tests detect both antibodies to the virus as well as the virus itself. The RNA tests screen for viral RNA, so they also detect the virus directly, and DNA tests look for copies of the viral RNA (since remember it’s a retrovirus so it copies its genetic material into DNA). For screening purposes, the recommended test is the antibody/antigen test, which is better at identifying early infection. It’s also recommended, if the first test is positive, to follow it with a confirmatory test that looks for antibodies or nucleic acids.

There’s currently no cure for AIDS; treatment, however, can help somebody with AIDS live longer, healthier lives and help reduce the risk of transmission. The primary method is to use of antiretroviral therapy ART. ART isn’t a single medicine, but a combination of medicines that is known as an HIV regimen. These help slow down HIV replication, which gives the immune system a chance to recover and help fight off other infections more effectively.