Pathogenesis of AIDS Flashcards
HIV infection stage is based on
age specifc CD4+ T cell count
CD4 T cell % of total Lymphocytes
Stage 0
early infection
recognized by HIV-test within 180 days of the first HIV+ test
meaning test positive within 180 days of the last negative test
stage 1
No AIDS-defining condition and a CD4 cell count at or above the cells/ul indicated per age
stage 2
No AIDS defining condition and a CD4 cell count at or above the cells/ul indicated per age
stage 3
AIDS
documented AIDS defining condition or CD4 cell count less than 200, 500 or 750 cells/ul indicated per age
Stage unknown
lab confirmation of HIv infection but no information on Cd4 cell count, CD4 cell percentage, or the presence of an AIDS-defining condition
Staging can be bidirectional given ….
no AIDS defining condition is present
AIDS defining illness in children under 6
Bacterial infections, multiple or recurrent
AIDS defining illnesses in adults, adolescents or children over 6yo
cervical cancer, invasive
Mycobacterium TB of any site, pulmonary
Pneumonia, recurrent
Phases of HIV infection
- Acute retroviral syndrome - weeks
- Chronic HIV - years to decades
- AIDS - Months to years
Acute retroviral syndrome
primary infection of cells in blood and mucosa
infection is then established in lymphoid tissues leading to viremia
Acute HIV syndrome when spread of infection throughout body
seroconversion - Anti HIV antibodies and HIV specific CTLs
Immune response
Chronic HIV
Clinical latency
establishment of chronic infection
virus trapped in lymphoid tissues by follicular DCs, low level of viral production
other microbial infections or cytokines can lead to increased viral replication
AIDS - phase
destruction of lymphoid tissue
depletion of CD4 T cells
Constitutional symptoms of ARS
fever*
chills*
fatigue*
Night sweats, anorexia and wt loss
Lymphatic symptoms of ARS
*Swollen lymph nodes especially in groin, head and neck
Nose and throat symptoms of ARS
*Sore throat, with or without ulcers or thrush
GI symptoms of ARS
Nausea
emesis
diarrhea
Musculoskeletal symptoms of ARS
Asymmetric joint swelling and tenderness
*myalgias
Neurologic symptoms of ARS
personality changes, headache, and painful, stiff neck
Rash characteristics of ARS
Maculopapular and primarily on trunk and/or proximal extremities
characteristics of oral lesions in ARS
thrush develops commonly on soft palate
early lesions also seen along gingival border
Reactivation in ARS
can reactivate HSV - cold sores
or VSZ - shingles
How can HIV enter the body?
blood
colon-rectum
vagina
What happens when HIV initially enters?
infects macrophages
How does HIV affect macrophages?
creates virus reservoir
infects the microglial cells of the brain, Pulmonary alveolar macs and Dendritic cells in skin
Causes macrophage dysfunction, virus release and cytokine release and dysregulation of immune function
Where do HIV travel for its latent period?
Lymph nodes
What happens upon increased viral load in the blood with regards to immunopathogenesis?
by this time, HIV has been able to infect CD4 T cells
if crosses the BBB leads to AIDS dementia
through CD4 ctyloysis causes
-immunodeficiency
-loss of B cell control - lymphadenopathy, hypergammaglobulinemia
-Loss of DTH (delayed type hypersensitivity) function - cutaneous infection and intracellular pathogens
what happens as a result of loss of T cell function?
severe systemic opportunistic infections
Kaposi’s sarcoma
Lymphoma
HIV causes ??? and what are the outcomes
-Lytic and latent infection of CD4 T cells
-Persistent infection of cells of macrophage family
-Disrupts neuron function
Outcomes are:
Immunodeficiency, AIDS dementia (crosses the BBB)
Briefly describe progression of untreated HIV
About 6 weeks after primary infection, CD4 T cell count falls drastically. At this same time, viral load peaks. This is acute HIV syndrome and there is wide dissemination of virus and seeding of lymphoid organs
small T cell count recovery around 12 weeks as viral load drop while virus enters latent period
over next 10-11 years, viral load slowly increases as CD4 count continues to slowly decrease
Constitutional symptoms appear 7-8 years
opportunistic infections occur as viral load increases exponentially
Death by year 10 -11
what happens due to loss of CD4 T cells during Chronic HIV?
through infection and loss of CD4 cells
- loss control of nonlymphoid cells
- loss of growth and control of B cells
- Growth and control of CD4 and CD8 T cells and NK cells - this leads to tumors and HIV progression
- loss of DTH which leaves vulnerable to intracellular organisms
what are some immunologic events affecting Macrophages and DCs during an HIV infection?
Macrophages carry HIV into CNS Excess secretion of cytokines in lymph nodes Decreased antigen presentation Decreased MHC II expression Decreased chemotaxis Decreased phagocytic ability Decreased cytotoxic ability
AIDS-dementia complex
(HIV/AIDS encephalopathy) results of HIV entering brain via microglial transport leads to: -memory loss -impaired cognition -impaired motor function -behavioral changes -Apathy -depression occurs as CD4 count falls to <200 cell/microliter
Due to Highly active anti retroviral therapy, ADC has
declined to <20% of those HIV+
may also improve mental function in those with ADC already
How does HIV evade the immune system?
- Antigenic drift of gp120 - evades antibody detection
- Heavy glycosylation of gp120 - evades antibody detection
- Infection of lymphocytes and Macrophages - inactivation of key element of immune defense
- Inactivation of CD4 helper cells - loss of activator of immune system and delayed type hypersensitivity
what are the possible outcomes of HIV infections?
rapid progression - AIDS in 2-3 yrs
typical progressors - AIDS in 10 yrs
Long-term nonprogressors - low HIV levels, normal CD4 T cells >10 yrs after HIV positive - BM transplant case (usually HIV-2 or HIV-1 ??)
Highly exposed persistently seronegative patients - infected but no HIV antibodies or HIV-RNA detected
Describe M-Tropic (R5)
Initial stages of infection mediated by R5
Macs and DCs are persistently infected and major reservoirs and means of distribution (Trojan Horses)
Targeting of CCR5 expressing T cells depletes GALT of CD4 T cells - lyse
Deficient CCR5 receptor pts more resistant to HIV infection and CCR5 in binding target for antiviral drugs
Describe T-Tropic (X4)
change in receptor preference to CXCR4 occurs late and correlates with progression of disease
Mutation of ENV gene for gp120 shifts tropism from R5 to X4
some viruses use both R5X4 receptors
Development of symptoms of AIDS
what is occuring pathology wise during development of symptoms of AIDS?
correlates with increased release of virus into the blood
increase in X4 virus
decrease in CD4 T cells
subsequent decrease in total T cell numbers (CD3 bearing cells) due to the lack of helper function
CD4 expressed
on surface of CD4 T lymphocytes (helper) and macrophages (including dendritic cells)
CCR5 expressed
on CD4+ T lymphocytes and macrophages
CXCR4 expressed on
CD4+ T lymphocytes and T cell lines
HIV-2 is less _____ than HIV-1
pathogenic
most HIV-2 pts are long term non progressors
longer asymptomatic stage, slower decline in CD4 T cell count
lower mortality rate due to AIDS
pts with HIV-2 are less infectious in early stages but trasmission rate increases as disease progresses
HIV-2 was more difficult to monitor but
in 2014, first FDA licensed viral load assay to detect HIV-2 nucleic acid was approved
Treatment of HIV-1 vs. HIV-2
some drugs for HIV-1 are not effective for HIV-2
HIV-2 is intrinsically resistant to Fusion inhibitors and non-nucleoside reverse transcriptase inhibitor based regimens
List some Antiviral therapies
Nucleoside Analogue reverse transcriptase inhibitors
Non nucleoside reverse transcriptase inhibitors
Protease inhibitors
Binding and Fusion inhibitors
Integrase inhibitors
A small number of ppl are resistant to infection because
have mutations in genes encoding CCR5 and/or CXCR4 co receptors
CCR5delta32 mutation - leads to a truncated protein with loss of extracellular component
-Homozygous mutation - immune
-Heterozygous mutation - decreases chances of infection, slows disease progression
Out of ppl who are naturally HIV immune, they were found to carry
gene called HLA B57
leads to larger production of CD8/killer cells
CTLs are cross reactive - attack more than one epitope associated with HIV including mutants that arise
contributes to strong response towards viruses that rapidly evolve
increase susceptibility to autoimmune diseases, in which T cells attack the body’s own cells
Mucosal immunity generated by frequent ______
sexual exposure to HIV
meaning immunity generated by cells lining the genital membranes prevented infection
Cells of macrophage lineage include
monocytes macrophages alveolar macs of the lung dendritic cells of skin microglial cells of brain
