JUMA HIV ONLY Flashcards
Outline 3 mechanisms of direct cell death caused by HIV
- Budding of newly formed virions through the T cell membrane stresses the plasma membrane, leading to cellular damage and contributing to apoptosis.
- Expression of viral proteins such as Vpr and Tat disrupts host cell metabolism, induces oxidative stress, and triggers apoptosis.
- Syncytia formation, driven by HIV envelope glycoprotein-mediated cell fusion, leads to rapid T cell death.
what is the “set point” in the context of HIV infection?
“set point” refers to the relatively stable level of HIV RNA (viral load) in the blood after the acute phase of infection and before the progression to AIDS.
It represents a balance between HIV replication and the immune system’s ability to suppress it.
A higher set point is associated with faster disease progression to AIDS, while a lower set point correlates with slower progression
What is meant by seroconversion?
Seroconversion refers to the development of detectable antibodies against HIV antigens. The timing of seroconversion following infection with HIV depends upon the sensitivity of the serologic test. As serologic tests have become more sensitive, most persons with HIV have documented seroconversion during early infection (ie, within the first several weeks after infection)
Describe the changes that occur in CD4+ T cell count and viral load in the acute phase of HIV infection
(1) Initial infection leads to a rapid decline in CD4+ T cell count, primarily in mucosal lymphoid tissue -> direct viral cytopathic effects, and immune-mediated killing.
(2) This is accompanied by a sharp rise in viral load, as HIV rapidly replicates and temporarily outpaces the immune response.
(3) Acute HIV syndrome may occur due to widespread viral
dissemination and immune activation.
(4) CD8+ cytotoxic T lymphocytes (CTLs) mount a strong response, leading to partial viral suppression.
(5) By week 6, viral load declines but is not fully eradicated, and CD4+ T cell count begins to recover.
(6) The infection then transitions into the chronic phase, characterized by clinical latency, where viral replication persists at lower levels and CD4+ T cell decline continues gradually over time –> This phase is typically asymptomatic
What is meant by the window period in HIV infection?
The window period is the time between initial HIV infection and when HIV testing techniques can reliably detect the virus in the blood, either through antigen detection, antibody recognition, or nucleic acid testing, depending on the test used.
Describe the ELISA Ag/Ab test for HIV
ELISA (Enzyme-Linked Immunosorbent Assay) involves coating a plate with either an antigen or antibody of interest. A blood sample is then added, allowing any target antigen or antibody present in the sample to bind to the coated surface. A second antibody (or antigen), which is linked to an enzyme, is then introduced to bind to the captured target. The addition of a substrate causes a color change due to the enzyme reaction. This color change is measured to determine the presence and quantity of the target antigen or antibody, yielding a positive or negative result.
Describe the structure of HIV
-HIV is a single-stranded (ssRNA), positive-sense retrovirus.
-It has a diploid genome, meaning it carries two identical copies of ssRNA.
-The genome is stabilized by a nucleocapsid.
-The genome, nucleocapsid, and essential viral enzymes (including integrase and reverse transcriptase) are enclosed within a capsid composed of the p24 protein.
-Surrounding the capsid is the matrix protein p17, which provides structural integrity.
-The virus is enclosed by a lipid envelope, derived from the host cell’s plasma membrane, which is studded with glycoproteins gp120 and gp41. These glycoproteins are crucial for viral entry into host cells.
Describe 3 ways by which HIV evades eradication by the immune system
*HIV is a retrovirus meaning it can undergo reverse transcription to produce double stranded DNA from its ssRNA. Its integrase enzyme can incorporate it into the host cell genome forming a provirus which remains as a permanent component of the host genome. This allows it to remain latent and evade immune detection.
*HIV is highly mutable. The high mutation rate of HIV is primarily due to the error-prone process of reverse transcription, which leads to a rapid evolution of the virus. This variability allows HIV to escape immune detection by altering the gp120 protein, which is the main target for immune recognition. Additionally, this variability enables HIV to develop resistance to some antiretroviral drugs over time.
*HIV can form reservoirs within lymphoid tissue and remain dormant there for years. Lymphoid tissues are more immunologically privileged and so HIV can go undetected here.
Nucleoside reverse transcriptase inhibitor MOA
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) are analogues of natural nucleosides that get incorporated into the growing viral DNA strand during reverse transcription. Some NRTIs, such as zidovudine (AZT), are thymine analogues. Once incorporated, they inhibit reverse transcriptase because they lack the 3’-OH hydroxyl group necessary for forming the phosphodiester bond with the next nucleotide. This results in premature termination of viral DNA synthesis
Emtricitabine, Lamivudine, Abacavir
Why is Tenofovir alafenamide fumarate (TAF) considered less toxic than Tenofovir disproxil fumarate (TDF)?
TDF is phosphorylated within the blood stream before being taken up by the cells. This means there are higher plasma levels of active drug which increases risk of toxicity particularly to bones and kidneys.
TAF on the other hand is phosphorylated intracellularly and so there is a lesser amount of active drug in the plasma.
MOA of Non-nucleoside RTI’s (NNRTIs)?
NNRTI’s work by directly inhibiting reverse transcriptase by binding to its active site and preventing its conformational change that is needed to carry out transcription of RNA to DNA.
Explain the mechanism(s) by which tenofovir causes nephrotoxicity/ bone mineral density loss
Nephrotoxicity
Tenofovir accumulates within the epithelial cells of the renal tubule- particularly in the PCT- and causes mitochondrial dysfunction through inhibition of DNA polymerase-gamma. This results in loss of ATP production, oxidative stress and eventual apoptosis.
BMD loss
(1)Tenofovir reduces phosphate resorption in the renal tubules by inhibiting the sodium-phosphate co-transporters. This causes phosphaturia and hypophosphatemia. Phosphate is necessary for the formation of hydroxyapatite therefore is needed for homeostasis in bone formation.
(2) Tenofovir can also reduce the activation of vitamin D by 1-alpha hydroxylase in the kidney which causes a reduced absorption of calcium from the intestine leading to increased PTH release causing increased bone resorption.
