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Flashcards in HIV Deck (37):

AIDS/HIV structure and function

-Immune dysregulation (deficiency and hyperactivation)
-Selective infection of CD4 cells (T cells and mono/macs)
-GP120 transmembrane glycoprotein for binding to CD4/co-receptor (CCR5 or CXCR4)
-GP120 surrounded by carbohydrate shield, which we make Abs against but they aren't neutralizing
-p24 capsid containing reverse transcriptase (creation of cDNA), integrase (migration and integration of cDNA into host genome), and protease (required for cleavage of viral proteins after release and activation of new viruses)
-3 genes that are all polycistronic: gag (structural proteins), pol (polymerase/integrase proteins), and env (surface envelope proteins)


Variability btwn HIVs

-Not all HIVs are equal, there is variability in mutation rate and virulence
-Virus mutates much faster than the TCR can keep up with


Host cell compliance

-HIV requires some host cell functions for survival
-Cell receptors that are required for host cell (CD4, CCR5, CXCR4)
-Biochemical pathways (such as ubiquitin)
-Transcription factor activation for protein synthesis
-Unique aspect of HIV: targets the only cells that can stop the virus (T cells/macs)
-Virus replication can remain quiescent for years until the cell is activated and transcription begins, resulting in the creation of viruses w/ in the cell


Spread of HIV

-Release of cell-free virus
-Exosome-mediated transmission
-Cell-cell transfer (most efficient, more rapid, evasion of host defenses)
-Sexually-transmitted HIV employs CCR5 as co-receptor


Life cycle (cell-free viral transmission)

-GP120 binds to CD4 then co-receptor (either CCR5 or CXCR4)
-Capsid enters the cell after membrane fusion, reverse transcriptase makes cDNA out of the viral RNA
-Integrase moves cDNA to nucleus and integrates it into host genome (into sites that are transcriptionally active)
-Host TFs will transcribe the viral DNA and make viral proteins out of the resultant RNA
-The viral RNA and proteins are packaged up into immature virions, which bud off the cell taking the membrane w/ them
-The virions then use protease to cleave the proteins inside the virus, thus activating the virus for another round of infection


Cell-cell transfer of HIV

-Presentation of HIV in trans from uninfected dendritic cells to T cells
-Env-induced, actin dependent synapse formation btwn infected and uninfected cells


HIV infection: acute phase

-Primary lytic targets of HIV are CCR5+ (activated) memory CD4 T cells (Th1 effectors)
-Most T cells in blood are not activated (CCR5-), but these are infected as well
-Within 14 days of acute infection 50% of all T cells are gone
-Most of these are GI mucosa associated
-Initially there is a large spike in HIV viruses in blood (congruent w/ sudden drop in T cell count), but then the virus level falls and remains steady for years (usually)


HIV infection: chronic phase

-10 billion viruses are produced (and most destroyed) daily
-1 billion CD4 T cells destroyed (and most replaced) daily
-W/ single drug Rx the WT virus is replaced by drug-resistant virus after 14 days
-Most virus-infected T cells are destroyed quickly (2 days), but resting CD4 central memory T cells can be infected and they take decades to eliminate (major reservoir for virus)
-Therefore we cannot get rid of the chronic infection due to resting central memory CD4 T cells


Retroviral restriction factors

-There is a difference in susceptibility to retroviruses even when using similar receptors and co-receptors
-Human gene products that inhibit retrovirus replication
-APOBEC3 family of nucleic acid editing nzs generate C->U in retroviral cDNA and induces fatal mutations
-However, HIV Vif binds to and inhibits APOBEC3


HIV immune evasion

-Low spike (GP120) density on virion surface (about 30)
-Glycan shielding of critical epitopes (GP120)
-Env heterogeneity and glycosylation (different from virus to virus)
-Preferential infection of HIV-specific T cells
-Vif to inhibit APOBEC3
-Nef decreases CD4 expression, blocks apoptosis
-Vpr: suppresses 12 production form monos
-Vpu inhibits tethering and NKT cell activation
-Escape mutants (high mutation rate): CTL generation cannot keep up w/ mutation rate of HIV
-Virion expression of host complement regulatory proteins (stops complement from binding to membrane)
-Chronic infection exhausts T cells
-Monos and T cells archive the virus


HIV-induced immune deficiency

-Rapid and early destruction of 50% of mucosal memory T cells (either by direct cytotoxicity or syncytia formation)
-Direct cytotoxicity: activation of DNA-dependent protein kinase during integration
-Synctia formation: uninfected + infected T cells fuse to form large cell that is non-functional
-Decreased BM production of lymphoid precursors
-Decreased thymic output of new T cells
-Eventual destruction of lymph node architecture-> impaired clonal expansion


Pathophysiology and pathogenesis of HIV

-Infection almost always occurs across mucosal barriers (using CCR5)
-Require CD8 T cells to eliminated virus infected cells
-CNS microglial (CD4 macrophages in brain) infection leads to neuro-encephalopathy
-Inappropriate/uncontrolled immune activation leads to proliferative disorders and systemic cytokine effects (sickness behavior)
-T cell deficiency and dysfunction lead to opportunistic infection (OI), the major cause of death


Determinants of clinical manifestation

-Inoculum, route of exposure, invasiveness, virulence
-Cell/tissue tropism, immune avoidance and subversion
-Integrity of physical/anatomic barriers
-Prior immunization/exposure
-Immune responses


Difficulty in HIV vaccination

-Immunologic correlates of protection are unknown
-Lack of animal studies
-Immune evasion factors impair use of broadly neutralizing Abs
-Neutralizing Abs arise in vivo only after multiple rounds of B cell maturation
-What to use as immunogen


HIV epidemiology

-2/3 of all HIV in sub-sarahan Africa (22.5 million)
-33 million people world wide w/ HIV/AIDS
-Infects mostly blacks, whites, latinos (in US), but blacks have 46% of all HIV cases while being only 12% of the US population
-Major sources of transmission: male-male sex, IV drug use, heterosexual sex


HIV testing recommendations

-Routine screening for all people 13-64
-Additionally test all patients who have been treated/tested for STD, initiating TB Rx, pregnant women, women w/ undocumented HIV status at L&D
-Annual screening for those at high-risk
-The 20% of people who are unaware they have HIV cause 50% of new HIV infections


HIV tests

-HIV Ab tests (standard, rapid, home)
-HIV Ag/Ab test
-Viral load
-CD4 T cell count


Standard Ab tests

-ELISA (ran 2 times) tests the Ab to all HIV proteins
-Used in screening
-Western blot: measures Abs to 8 main HIV genes: of Gag, Pol, and Env (2/8 must be positive)
-WB is the definitive test for confirmatory Dx


Clinical definitions

-CD4 count: surrogate marker of immune function (normal 500-1500), strongest predictor of disease progression, prognosis, survival
-AIDS: CD4 count <14%
-Viral load (HIV RNA by PCR): quantifies virus in blood, surrogate marker for Rx response


Progression of test result patterns

-HIV RNA will be positive 1-2 wks after infection
-Architect test (looking at p24Ag) will be positive after 2-4 wks
-ELISA will be positive after 4-6 wks (so there is a 4-6 wk period from when infection occurs to when a tested person will be positive)
-WB won't be positive until 2 mo after infection
-All tests will be negative at time of infection unless prior exposure


Acute HIV manifestations

-Fever, pharyngitis, rash (maculopapular on face, trunk, extremities) w/ mucocutaneous ulceration, lymphadenopathy, myalgia/arthralgia, diarrhea/nausea, headache
-Onset about 6 wks after infection, duration for 2-8 wks (if symptoms progress in severity it may correlate w/ rapid progression)


Different forms of progression

-Rapid progressor: acute symptoms become more severe and death occurs shortly after acute phase (about 2 years)
-Intermediate progressor (most common): acute symptoms subside and people live for about 10 years
-Elite controller (late progressor): acute symptoms subside and person can live for decades (rare)


Chronic symptomatic HIV

-Fever for greater than two weeks
-Diarrhea for greater than 1 mo
-Onychomycosis of fingernails
-Seb derm (or other skin infections)
-Syphilis or other STIs
-Oral hairy leukoplakia (EBV infection associated w/ HIV)
-Candida infections of vagina in females
-Herpes zoster (shingles)
-Rx of OHL and VZV is acyclovir for both


Chronic symptomatic HIV in women

-Same as in men but also:
-Recurrent vulvovaginal candidiasis
-Cervical dysplasia
-Carcinoma in situ of cervix
-Pelvic inflammatory disease


Characteristics of AIDS

-Pneumocystis pneumonia (PCP)
-Kaposis sarcoma (HHV8, independent of CD4 #)
-Pseudomonas pneumonia (recurrent)
-CMV retinitis
-Many other OIs
-CD4/CD8 ratio will be flipped so that CD8 will be 2-3x more then CD4 (usually there are more CD4 cells)


Pneumocystis pneumonia (PCP)

-May mimic TB (fevers, chills, night sweats, weight loss, SOB)
-CXR can be classic (diffuse bilateral interstitial) or atypical (pneumatoceles, pneumothorax)
-Dx: LDH 400-500, sputum for PCP
-Rx: bactrim or atovoquone


CMV retinitis

-Usually when CD4 <50
-Starts as unilateral, then bilateral if untreated
-May be asymptomatic (or decreased acuity, field defects)
-Retinal exam shows hemorrhage and exudate (cottage cheese and ketchup)
-Rx is antiviral gancyclovir
-Prevention w/ eye exams


Headaches in AIDS pts

-Could be due to: cryptococcus, toxoplasmosis, lymphoma, syphilis, herpes, CMV, PML, viral or bacterial meningitis
-Toxo, lymphoma, and PML likely to have focal neurologic presentation


CNS mass lesions

-Due to toxoplasmosis: multiple ring enhancing lesions
-Lymphoma: typically solitary ring enhance lesions


HIV Rx basics

-Always a cocktail (to avoid drug resistance generation)
-Usually 2 nucleoside inhibitors and a protease inhibitor
-As long as the meds are taken no drug resistance should occur and the viral load should be controlled
-Drug resistance found in 10% of HIV pts who have never take anti-retroviral therapy (ART)
-ART is recommended for everyone w/ HIV


Immune reconstitution inflammatory syndrome (IRIS)

-Inflammatory response to an infection or malignancy that occurs early during effective ART w/ increasing CD4 levels
-Can occur during Rx for infection or in response to an unrecognized pre-existing infection (unmasking)


Nucleoside reverse transcriptase inhibitors (NRTIs)

-Nucleoside analogs that must be phosphorylated intracellularly to be active
-Compete w/ natural nucleosides for incorporation into growing DNA chain
-Terminates DNA chain elongation after incorporation
-Renally excreted
-Emtricitabine (FTC) has no major issues
-Tenofovir (TDF) can cause rare fanconi syndrome (1%) and greater loss of bone density


Protease inhibitors

-All combined ritonavir (inhibits CYP3A4), the drugs ritonavir is partnered with are metabolized by CYP3A4
-Atazanavir (ATV) major issues include increased bilirubin and PR prolongation (heart problem)
-Darunavir (DRV) major issue is a rash
-High resistance barrier: require multiple mutations to be resistant
-All end in "navir"


Non-nucleoside revers transcriptase inhibitors (NNRTIs)

-Efavirnez (EFV) is limited in use due to severe CNS effects, also causes a rash, hypersensitivity, and is a possible teratogen
-All NNRTIs are inducers of CYP3A4
-Only a single viral mutation is required to generate resistance


Integrase inhibitors

-Generally well tolerated, only a single mutation is required to generate resistance (except to DTG)
-Dolutegravir (DTG) is taken once a day, doesn't require boosting, and has less potential for resistance
-All end in "gravir"


ART guidelines

-Want to take 2 NRTIs (FTC+TDF) plus one of the following: protease inhibitor, NNRTI, DTG


Response to Rx

-HIV RNA <50 by week 24 (mostly undetectable)
-If this is not accomplished there is virology failure and they should be screened by viral genotyping for dry resistance
-Adherence critical to ensuring drug resistance does not occur, even not taking 1 of the 3 drugs will lead to resistance to all of them
-Resistance to one drug leads to cross resistance to all, then must change up the regimen
-First regimen always has highest success rate, success falls off with each new regimen