HIV Flashcards
describe the immunology of HIV
The effects of HIV infection can be ascribed to the immune deficiency which develops in infected
patients. The virus has a surface glycoprotein (gp120) which binds to CD4 glycoprotein on the surface
of host cells. The most important target for the virus is the CD4 bearing lymphocyte (the T-helper
lympho- cytes) which the virus infects and subsequently destroys. The progressive destruction of the
CD4+ lymphocyte population corresponds to disease progression from HIV infection. The normal CD4
lymphocyte count is 500-1500 cells/mm3 and a patient is often asymptomatic from HIV infection until
the count has fallen to <200 cells/mm3. It is below this level that the patient’s risk of opportunistic
infection and tumour disease rises dramatically.
what does HIV infect?
HIV infects and destroys cells of the immune system especially the T-helper cells that are CD4+. CD4 receptors are not exclusive to lymphocytes, they are also present on the surface of macrophages and monocytes, cells in the brain, skin, and probably many other sites.
symptoms and signs of HIV progression
weight loss
lymphadenopathy
thrush
skin and oral disease
when should antivirals start in a patient with HIV?
CD4 lymphocyte cell count (normal 500-1500): Patients should be started on antivirals if CD4 count <350. Start PCP prophylaxis when count <200. The absolute cell count can fall in a healthy patient with an intercurrent infection so a “one off” cell count should not form the basis for treatment but rather a series of results.
describe how the viral load of HIV changes
initially high during acute infection
falls to a low level
rises again in later stages after on average 6-8 years
how can you quantify HIV viral load?
PCR to measure the number of RNA copies/ml blood
if the viral load of HIV is not suppressed to <40 copies/ml what should you do?
consider changing to a more potent/effective combination of antivirals
how can disease progression of HIV be influenced?
Age
HLA type
hx of seroconversion illness
theories of HIV infection
Evidence shows that co-factors are needed in the attachment of HIV to the CD4 cells (i.e., factors
similar to but distinct from the CD4 receptor). The chemokine receptor 5 (CCR-5) has been widely
studied. Patients with a mutation of both CCR-5 alleles appear to be very resistant to HIV infection.
HIV-infected patients who have a single CCR-5 allele mutant appear to have a slower rate of HIV
disease progression compared to others. CCR-5 is now a target for drug treatment.
a new class of antivirals are being developed called fusion inhibitors. what do these do?
block the attachment of the virus to the cell wall by blocking GP41
describe primary HIV infection
This is similar to glandular fever with rash, fever, pharyngitis and lymphadenopathy predominant. Some patients develop diarrhoea, meningitis or neuropathy. The illness is self-limiting, and blood should be taken early in its course (acute phase serum) and during the convalescent period to test for HIV antibody. The early sample will be antibody negative but antigen positive and the late sample will usually be antibody positive although this may take up to three months to develop after the illness. HIV viral load testing is sufficiently sensitive to allow detection of HIV during seroconversion and before the development of antibodies. A severe or prolonged seroconversion illness is now recognised as a poor prognosticator which correlates with more rapid disease progression.
describe the process of reverse transcription
Once the virus penetrates the host cell it releases its RNA which must be converted to DNA to allow incorporation into the host genome. This process is known as reverse transcription and requires the enzyme reverse transcriptase.
give examples of reverse transcriptase inhibitors
zidovudine (AZT) didanosine (ddl) zalcitabine (ddC0 lamivudine (3TC) stavudine (d4T) abacavir
what other tissues do transcriptase inhibitors work on and what may this cause?
nucleoside analogues and therefore interfere with the function of many healthy host cells including marrow cells, as a consequence of which marrow toxicity is a frequently encountered adverse effect.
describe AZT
AZT was the first drug to be licensed for treatment of HIV infection. It remains useful despite increased
recognition of its limitations. It is particularly valuable in reducing transmission of infection from
mother to infant during pregnancy and in stopping the development of AIDS dementia (AZT
penetrates the blood brain barrier better than many other drugs of the same group).
what class of drugs are used in combination with nucleoside analogues in first line treatment?
non-nucleoside reverse transcriptase inhibitors
discuss the effect and side effects of non-nucleoside reverse transcriptase inhibitors
They act on the reverse transcriptase enzyme (at a different site from the nucleoside analogues) and are sometimes better tolerated than nucleoside analogues. The commonest side effect being vivid dreams/nightmares when taking the drug efavirenz.
name a non-nucleoside reverse transcriptase inhibitor
efavirenz
how do protease inhibitors work
inhibit the virus protease enzyme which cleaves polyproteins into proteins required for viral maturation
what are protease inhibitors usually used in combination with?
reverse transcriptase inhibitors
common side effect of protease inhibitors
raised cholesterol
name the drug classes used for treatment of HIV
nucleoside analogues non-nucleoside reverse transcriptase inhibitors protease inhibitors integrase inhibitors chemokine receptor antagonists fusion inhibits
how to integrase inhibitors work?
prevent viral DNA integrating into the CD4+ cell chromosome
give an example of an integrase inhibitor
graltegravir
