Lecture 59 to 60: HIV Flashcards
HIV: retroviruses
- RNA- dependent DNA polymerase (reverse transcriptase [RT]), replicate through a DNA intermediate,
- Virulence factors: Syncytin: captive retroviral envelope
- Etiopath
- Simple retroviruses encode gag, pol, and env genes;
- Complex viruses have more open reading frames to encode accessory genes (HIV: tat, rev, nef, vif, vpu)
- Lentiviruses: slow viruses assoc. with neurologic and immunosuppressive disease
- Gag: group-specific antigen (core and capsid proteins)
- Pol: polymerase (reverse transcriptase, protease and integrase)
- Env: envelope (glycoproteins)
- Other HTLV and HIV specific genes
- Class VI virus:
- 2 copies (+)RNA: non-infectious,virus associated premade Reverse Transcriptase generates ds provirus
- Provirus: integrates into host genome, template for synthesis of viral mRNA
- differences bw HPV
- HIV: integration is part of nl life cycle
- HPV: integration terminates life cycle
- Viral mRNA: viral non-structural and viral structural proteins
HIV Lifecycle
Binding & Fusion -> RT -> Integration -> Transcription -> Assembly -> Budding
HIV Pathogenesis
- Major determinant: virus tropism for CD4- expressing T cells and macrophage lineage cells
- multipotent hematopoietic stem and progenitor cells
- results in long period of clinically silent but dynamic virus replication + diversification w/ high host cell turnover
- decimates helper and DTH functions of the immune response
- AIDS-defining opportunistic infections and tumors occur when CD4+ T cell numbers fall below a level that can sustain immunity
- HIV enters the body in infected macrophages
- Dendritic cells
– Accumulate the virus particles on their surfaces, but do not usually internalize them
– carry virus to lymph nodes resulting in efficient infection of CD4+ T cells
- Present in most compartments in the body (with varying concentrations)
**Hematopoietic Stem Cell (HSC)-based HIV reservoir might well be permanent, no matter how small in size
- Cells appear to be the result of syncytial fusion of HIV-infected macrophages and microglia; Syncytia often seen in the brain
- Cell to cell viral spread; immune circulatory antibodies cannot have an effect
HIV: mechanism of immune evasion
– antigenic variation
– carbohydrate masking of target epitopes
– conformational changes by viral envelope to mask neutralization targets
– downregulation of host HLA
– viral latency in resting T cells and antigen- presenting cells
HIV: Rx, prevention, control
- Highly active antiretroviral therapy (HAART): effective anti-retroviral in reducing viral load & global infections
- GOAL: GET HIV RNA LEVEL BELOW ASSAY DETECTION LIMITS
- Pt taken off HAART: viral load immediately starts going back up. It did not take too long to stop that testing, as it was clear the virus is kept in check by the proper antiretrovirals. -> concept of reservoir
HIV Viral load
- Can be as high as 750 K copies/ml (not absolute)
- Suggestive of how rapidly progression of disease occurs
Course of HIV progression
- Typical progression – 80%, 7-10 yrs
- Rapid progression – 5-10%, within 2 yrs
- Non-progression
- – 10-15%, no disease ~7-10+ yrs
- – CD4 count stays high, viral load not detectable (no medications)
- Clinical latency period: bw acute HIV syndrome/dissemination & constitutional sx (see image below)
– Negative HIV test (primary infection to sero- conversion)
– Viral load very high, incr high transmission risk
Acute retroviral syndrome
– Symptoms can have a huge range
– WIDE DIFFERENTIAL DIAGNOSIS
Opportunistic infections
– GOAL is to prevent these from occurring
– Greatly increase chance of death
AIDS
- final stage of HIV infection
- – virus has weakened the immune system to the point at which the body has a difficult time fighting infection
- One or more specific infections, certain cancers, and / or a very low number of T cells resulting in AIDS
- Progression of AIDS
1) acute infection
2) strong anti-HIV immune defense
3) a latent reservoir
4) loss of CD4+ cells and loss of immune response
5) onset of AIDS
Infections associated w AIDS
- bacterial pneumonia: strep pneumoniae (pneumolysin, IgA protease)
- mycobaterium: M. avium & intracellulare complex (MAC)
- Night sweats, weight loss, abdominal pain, fatigue, diarrhea and anemia
- salmonellosis
- bartonella henselae
- Bacillary angiomatosis: vascular proliferative disease in immunocompromised patients; purplish to bright red skin patches, often resembling Kaposi’s sarcoma
- Infection primarily involves skin, lymph nodes, or liver and spleen
- Subacute endocarditis
- Cat-scratch disease: chronic regional lymphadenopathy assoc. w/ cat scratch
- Viral heptatitis
- CMV
- HHV-1 & 2
- HPV
- PML: JC virus
- speech problems
- weakness on one side of the body
- loss of vision in one eye
- numbness in one arm or leg
- KSHV: ONE OF THE MOST FREQUENTLY DETECTED TUMORS IN AIDS PATIENTS
- Usually appears as pink, red or purple lesions on the skin and mouth (with darker skin, the lesions may look dark brown or black)
- Rx: alpha-interferon
- NHL:
- HTLV-1, Hep C, and EBV, ↑ risk of developing non-Hodgkin’s lymphoma
- Cryptococcal meningitis: Lung - widened alveolar septum w/few inflammatory cells and numerous yeasts
- Pneumocystis jirovecii (formerly P. carinii, PCP)
- T. gondii: Ring-enhancing lesions on CT scan
- Cryptosporidium: ingestion of contaminated food, water
- Leads to severe, chronic diarrhea in people w/ AIDS
- self-limited syndrome in HIV-infected individuals w/ CD4 counts > 200
CD4+ levels for different infections in HIV+
- 200 to 500: Candidia, cryptosporidum, tb
- 100 to 200: pneumocystis,
- 50 to 100: histoplasmosis, toxo, B. henselae
- <50: cryptococcus, MAC, NHL, CMV, JC virus
4 groups of HIV meds
- rotease inhibitors
- integrase inhibtiors
- NRTI
- NNRT
JC virus
Serious brain infection caused by the human polyomavirus JC virus
- speech problems
- weakness on one side of the body
- loss of vision in one eye
- numbness in one arm or leg
– PML usually occurs only when the immune system has been severely damaged
CD4+ 200 to 500
Candidia, HHV-8, cryptosporidum, tb
CD4+ 100 to 200
pneumocystis
CD4+ 50 to 100
histoplasmosis, toxo, B. henselae
CD4+ < 50
cryptococcus, MAC, NHL, CMV, JC virus
